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Abd El-Fattah AA, Hamid Sadik NA, Shahin AM, Shahin NN. Simvastatin and eugenol restore autophagic flux and alleviate oxidative, inflammatory, and fibrotic perturbations in an arginine-induced chronic pancreatitis rat model. Arch Biochem Biophys 2025; 768:110357. [PMID: 40015469 DOI: 10.1016/j.abb.2025.110357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 02/15/2025] [Accepted: 02/24/2025] [Indexed: 03/01/2025]
Abstract
Chronic pancreatitis (CP), a progressive inflammatory disease characterized by pancreatic tissue destruction and fibrosis, is considered a challenging health burden due to insufficiencies of current management procedures. Autophagy impairment has emerged as a major triggering event in pancreatitis, raising interest in exploring the potential of targeting autophagy as a possible interventional strategy. This study aimed to evaluate the possible ameliorative effect of two autophagy modulators, simvastatin and eugenol, on CP-related perturbations in an arginine-induced rat model. Repeated l-arginine administration (5 g/kg divided into 2 doses with a 1 h interval, given intraperitoneally every 3rd day for a total of 10 times) provoked CP features, demonstrated by acinar damage, oxidative stress, inflammation, and fibrosis. Arginine-triggered pancreatitis was accompanied by hampered pancreatic autophagic flux, evidenced by overexpression of pancreatic p62 and LC3-Ⅱ and downregulation of pancreatic AMPK and LAMP-1 mRNA expression. Treatment with simvastatin (20 mg/kg, intraperitoneally 24 h, before each arginine dose) and eugenol (50 mg/kg/day orally for 30 days) achieved significant anti-oxidative, anti-inflammatory, and anti-fibrotic effects, and reversed the arginine-instigated autophagic blockade, with superior ameliorative effects attained by eugenol. Altogether, simvastatin and eugenol provide a promising interventional approach for CP, at least partly, by restoring the impaired autophagic flux associated with CP.
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Affiliation(s)
| | | | - Ahmad Mustafa Shahin
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Nancy Nabil Shahin
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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Guo W, Zhou H, Wang J, Lu J, Dong Y, Kang Z, Qiu X, Ouyang X, Chen Q, Li J, Cheng X, Du K, Li M, Lin Z, Jin M, Zhang L, Sarapultsev A, Shi K, Li F, Zhang G, Wu K, Rong Y, Heissmeyer V, Liu Y, Li Y, Huang K, Luo S, Hu D. Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2308307. [PMID: 39166458 PMCID: PMC11336898 DOI: 10.1002/advs.202308307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 05/12/2024] [Indexed: 08/23/2024]
Abstract
Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non-small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome-1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO-induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti-PD-L1/TGF-β bispecific antibody in inhibiting LLC-derived subcutaneous tumor models. Thus, ALO is first identified as a novel late-stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A.
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Affiliation(s)
- Weina Guo
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
- Department of Laboratory MedicineWuhan Children's Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Haifeng Zhou
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Jingbo Wang
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Junjie Lu
- Xiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyang441000China
| | - Yalan Dong
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Zhenyu Kang
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Xiaoyuan Qiu
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Xiaohu Ouyang
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Qianyun Chen
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Junyi Li
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Xiang Cheng
- Hubei Key Laboratory of Biological Targeted TherapyUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China
| | - Keye Du
- Department of NeurosurgeryUnion Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Mingyue Li
- Department of GastroenterologyZhongda Hospital, Southeast UniversityNanjing210000China
| | - Zhihao Lin
- Institute of Neuroscience, School of MedicineXiamen UniversityXiamen361000China
| | - Min Jin
- Cancer CenterUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Lei Zhang
- Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan250014China
| | - Alexey Sarapultsev
- School of Medical BiologySouth Ural State UniversityChelyabinsk454087Russia
| | - Kuangyu Shi
- Department of Nuclear MedicineUniversity of BernBern3007Switzerland
| | - Fangfei Li
- Shum Yiu Foon Sum Bik Chuen Memorial Centre for Cancer and Inflammation Research School of Chinese MedicineHong Kong Baptist UniversityHong KongSAR999077China
| | - Ge Zhang
- Institute of Integrated Bioinfomedicine and Translational ScienceSchool of Chinese MedicineHong Kong Baptist UniversityHong KongSAR999077China
| | - Kongming Wu
- Department of OncologyTongji Hospital of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Yueguang Rong
- School of Basic Medicine of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Vigo Heissmeyer
- Institute for Immunology Biomedical CenterLudwig‐Maximilians‐Universität München82152Planegg‐MartinsriedGermany
| | - Yue Liu
- Cardiovascular Disease CenterXiyuan hospital of China academy of Chinese medical SciencesBeijing100102China
| | - Yunlun Li
- Affiliated Hospital of Shandong University of Traditional Chinese MedicineJinan250014China
- Innovation Research Institute of Traditional Chinese MedicineShandong University of Traditional Chinese MedicineJinan250355China
| | - Kun Huang
- School of Pharmacy of Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Shanshan Luo
- Institute of Hematology, Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Desheng Hu
- Department of Integrated Traditional Chinese and Western MedicineUnion Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
- Hubei Key Laboratory of Biological Targeted TherapyChina‐Russia Medical Research Center for Stress ImmunologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
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Zhang R, Zhu Z, Ma Y, Tang T, Wu J, Huang F, Xu L, Wang Y, Zhou J. Rhizoma Alismatis Decoction improved mitochondrial dysfunction to alleviate SASP by enhancing autophagy flux and apoptosis in hyperlipidemia acute pancreatitis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 129:155629. [PMID: 38677271 DOI: 10.1016/j.phymed.2024.155629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 03/24/2024] [Accepted: 04/09/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas, especially hyperlipidemia acute pancreatitis (HLAP) is the third leading cause of acute pancreatitis which is more severe with a greater incidence of persistent multiorgan failure. HLAP inflicts injury upon the organelles within the acinar cell, particularly mitochondria, the endolysosomal-autophagy system, and is accompanied by senescence-associated secretory phenotype (SASP). RAD, only two consists of Rhizoma Alismatis and Atractylodes macrocephala Rhizoma, which is best known for its ability to anti-inflammatory and lipid-lowering. Nevertheless, the mechanism by which RAD alleviates HLAP remains obscure, necessitating further investigation. PURPOSE The study aimed to assess the effects of the RAD on HLAP and to elucidate the underlying mechanism in vivo and in vitro, offering a potential medicine for clinical treatment for HLAP. STUDY DESIGN AND METHODS C57BL/6 mice with hyperlipidemia acute pancreatitis were induced by HFD and CER, then administrated with RAD. AR42J were stimulated by cerulein or conditioned medium and then cultured with RAD. Serums were analyzed to evaluate potential pancreas and liver damage. Furthermore, tissue samples were obtained for histological, and protein investigations by H&E, Oil red staining, and Western blot. In addition, western blot and immunofluorescent staining were utilized to estimate the effect of RAD on mitochondrial function, autophagy flux, and SASP. RESULTS In vivo, RAD considerably alleviated systemic inflammation while attenuating TC, TG, AMY, LPS, inflammatory cytokines, histopathology changes, oxidative damage, mitochondrial fission, and autophagy markers in HLAP mice. Impaired autophagy flux and mitochondrial dysfunction resulted in a significant enhancement of NLRP3 and IL-1β in the pancreas. RAD could reverse these changes. In vitro, RAD significantly restored mitochondrial membrane potential and oxidative phosphorylation levels. RAD decreased Beclin-1 and LC3-II expression and increased LAMP-1 and Parkin-Pink expression, which showed that RAD significantly ameliorated HLAP-induced damage to the mitochondria function by suppressing mitochondrial oxidative damage and enhancing autophagy flux and mitophagy to remove the damaged mitochondria. In addition, we found that RAD could up-regulate the expression of BAX, and Bad and down-regulate the expression of p16, and p21, indicating that RAD could promote damaged cell apoptosis and alleviate SASP. CONCLUSIONS This study revealed that RAD ameliorates mitochondrial function to alleviate SASP through enhancing autophagy flux, mitophagy, and apoptosis which provided a molecular basis for the advancement and development of protection strategies against HLAP.
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Affiliation(s)
- Rongzhan Zhang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Zhiyong Zhu
- Wuxi Huishan District People's Hospital, Wuxi, 214187, China; Affiliated Hushan Hospital of Xingling College, Nantong University, 226019, China
| | - Yumei Ma
- Digestive Department of Qinghai Provincial People's Hospital, Xining, 810007, China
| | - Tiantian Tang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Jiejie Wu
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Fang Huang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Luzhou Xu
- Gastroenterology Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210004, China
| | - Yaping Wang
- Wuxi Huishan District People's Hospital, Wuxi, 214187, China; Affiliated Hushan Hospital of Xingling College, Nantong University, 226019, China.
| | - Jia Zhou
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
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Tsomidis I, Voumvouraki A, Kouroumalis E. The Pathogenesis of Pancreatitis and the Role of Autophagy. GASTROENTEROLOGY INSIGHTS 2024; 15:303-341. [DOI: 10.3390/gastroent15020022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.
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Affiliation(s)
- Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
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Zhang T, Zhu S, Huang GW. ALKBH5 suppresses autophagic flux via N6-methyladenosine demethylation of ZKSCAN3 mRNA in acute pancreatitis. World J Gastroenterol 2024; 30:1764-1776. [PMID: 38617741 PMCID: PMC11008368 DOI: 10.3748/wjg.v30.i12.1764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 02/03/2024] [Accepted: 03/06/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Increasing evidence has demonstrated that N6-methyladenosine (m6A) RNA modification plays an essential role in a wide range of pathological conditions. Impaired autophagy is a critical hallmark of acute pancreatitis (AP). AIM To explore the role of the m6A modification of ZKSCAN3 in the regulation of autophagy in AP. METHODS The AP mouse cell model was established by cerulein-treated mouse pancreatic acinar cells (MPC-83), and the results were confirmed by the levels of amylase and inflammatory factors. Autophagy activity was evaluated by specific identification of the autophagy-related microstructure and the expression of autophagy-related genes. ZKSCAN3 and ALKBH5 were knocked down to study the function in AP. A m6A RNA binding protein immunoprecipitation assay was used to study how the m6A modification of ZKSCAN3 mRNA is regulated by ALKBH. RESULTS The increased expression of amylase and inflammatory factors in the supernatant and the accumulation of autophagic vacuoles verified that the AP mouse cell model was established. The downregulation of LAMP2 and upregulation of LC3-II/I and SQSTM1 demonstrated that autophagy was impaired in AP. The expression of ZKSCAN3 was upregulated in AP. Inhibition of ZKSCAN3 increased the expression of LAMP2 and decreased the expression of the inflammatory factors, LC3-II/I and SQSTM1. Furthermore, ALKBH5 was upregulated in AP. Knockdown of ALKBH5 downregulated ZKSCAN3 expression and restored decreased autophagic flux in AP. Notably, the bioinformatic analysis revealed 23 potential m6A modification sites on ZKSCAN3 mRNA. The m6A modification of ZKSCAN3 mRNA was significantly decreased in AP. Knockdown of ALKBH5 increased the modification of ZKSCAN3 mRNA, which confirmed that ALKBH5 upregulated ZKSCAN3 expression in a m6A-dependent manner. CONCLUSION ALKBH5 inhibits autophagic flux through m6A demethylation of ZKSCAN3 mRNA in AP, thereby aggravating the severity of the disease.
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Affiliation(s)
- Tao Zhang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410005, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410005, Hunan, China
| | - Shuai Zhu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410005, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410005, Hunan, China
| | - Geng-Wen Huang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410005, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410005, Hunan, China
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Yang J, Liu Y, Liu S. The role of epithelial-mesenchymal transition and autophagy in pancreatic ductal adenocarcinoma invasion. Cell Death Dis 2023; 14:506. [PMID: 37550301 PMCID: PMC10406904 DOI: 10.1038/s41419-023-06032-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 07/20/2023] [Accepted: 08/01/2023] [Indexed: 08/09/2023]
Abstract
Of all pancreatic cancer (PC) cases, approximately 90% are pancreatic ductal adenocarcinoma (PDAC), which progress rapidly due to its high degree of invasiveness and high metastatic potential. Epithelial-mesenchymal transition (EMT) is a prerequisite for cancer cell invasion and spread, and it is mediated by the specific cellular behaviors and the tumor microenvironment. Autophagy has long been a target of cancer therapy, and it has been considered to play a dual and contradictory role, particularly regarding EMT-mediated PDAC invasion. This review discusses the characteristics and the biological role of EMT and autophagy from a cellular perspective, explaining invasion as a survival behavior of PDAC, with the aim of providing novel insights into targeting EMT and autophagy to overcome PDAC invasion.
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Affiliation(s)
- Jian Yang
- Central Laboratory, The Third Affiliated Hospital, Qiqihar Medical University, Qiqihar, 161000, Heilongjiang Province, P.R. China
| | - Ying Liu
- Department of Medical Oncology, The Third Affiliated Hospital, Qiqihar Medical University, Qiqihar, 161000, Heilongjiang Province, P.R. China
| | - Shi Liu
- Central Laboratory, The Third Affiliated Hospital, Qiqihar Medical University, Qiqihar, 161000, Heilongjiang Province, P.R. China.
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Guo Y, Zhang X, Li J, Zhou Z, Zhu S, Liu W, Su J, Chen X, Peng C. TRAF6 regulates autophagy and apoptosis of melanoma cells through c-Jun/ATG16L2 signaling pathway. MedComm (Beijing) 2023; 4:e309. [PMID: 37484971 PMCID: PMC10357248 DOI: 10.1002/mco2.309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 07/25/2023] Open
Abstract
Autophagy and apoptosis are essential processes that participate in cell death and maintain cellular homeostasis. Dysregulation of these biological processes results in the development of diseases, including cancers. Therefore, targeting the interaction between apoptosis and autophagy offers a potential strategy for cancer therapy. Melanoma is the most lethal skin cancer. We previously found that tumor necrosis factor receptor-associated factor 6 (TRAF6) is overexpressed in melanoma and benefits the malignant phenotype of melanoma cells. Additionally, TRAF6 promotes the activation of cancer-associated fibroblasts in melanoma. However, the role of TRAF6 in autophagy and apoptosis remains unclear. In this study, we found that knockdown of TRAF6 induced both apoptosis and autophagy in melanoma cells. Transcriptomic data and real-time PCR analysis demonstrated reduced expression of autophagy related 16 like 2 (ATG16L2) in TRAF6-deficient melanoma cells. ATG16L2 knockdown resulted in increased autophagy and apoptosis. Mechanism studies confirmed that TRAF6 regulated ATG16L2 expression through c-Jun. Importantly, targeting TRAF6 with cinchonine, a TRAF6 inhibitor, effectively suppressed the growth of melanoma cells by inducing autophagy and apoptosis through the TRAF6/c-Jun/ATG16L2 signaling pathway. These findings highlight the pivotal role of TRAF6 in regulating autophagy and apoptosis in melanoma, emphasizing its significance as a novel therapeutic target for melanoma treatment.
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Affiliation(s)
- Yeye Guo
- Department of DermatologyXiangya HospitalCentral South UniversityChangshaChina
- National Engineering Research Center of Personalized Diagnostic and Therapeutic TechnologyChangshaChina
- Furong LaboratoryChangshaChina
- Hunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)ChangshaChina
| | - Xu Zhang
- Department of DermatologyXiangya HospitalCentral South UniversityChangshaChina
- National Engineering Research Center of Personalized Diagnostic and Therapeutic TechnologyChangshaChina
- Furong LaboratoryChangshaChina
- Hunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)ChangshaChina
| | - Jie Li
- Department of DermatologyXiangya HospitalCentral South UniversityChangshaChina
- National Engineering Research Center of Personalized Diagnostic and Therapeutic TechnologyChangshaChina
- Furong LaboratoryChangshaChina
- Hunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)ChangshaChina
| | - Zhe Zhou
- Department of DermatologyXiangya HospitalCentral South UniversityChangshaChina
- National Engineering Research Center of Personalized Diagnostic and Therapeutic TechnologyChangshaChina
- Furong LaboratoryChangshaChina
- Hunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)ChangshaChina
| | - Susi Zhu
- Department of DermatologyXiangya HospitalCentral South UniversityChangshaChina
- National Engineering Research Center of Personalized Diagnostic and Therapeutic TechnologyChangshaChina
- Furong LaboratoryChangshaChina
- Hunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)ChangshaChina
| | - Waner Liu
- Department of DermatologyXiangya HospitalCentral South UniversityChangshaChina
- National Engineering Research Center of Personalized Diagnostic and Therapeutic TechnologyChangshaChina
- Furong LaboratoryChangshaChina
- Hunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)ChangshaChina
| | - Juan Su
- Department of DermatologyXiangya HospitalCentral South UniversityChangshaChina
- National Engineering Research Center of Personalized Diagnostic and Therapeutic TechnologyChangshaChina
- Furong LaboratoryChangshaChina
- Hunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)ChangshaChina
| | - Xiang Chen
- Department of DermatologyXiangya HospitalCentral South UniversityChangshaChina
- National Engineering Research Center of Personalized Diagnostic and Therapeutic TechnologyChangshaChina
- Furong LaboratoryChangshaChina
- Hunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)ChangshaChina
| | - Cong Peng
- Department of DermatologyXiangya HospitalCentral South UniversityChangshaChina
- National Engineering Research Center of Personalized Diagnostic and Therapeutic TechnologyChangshaChina
- Furong LaboratoryChangshaChina
- Hunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityChangshaChina
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital)ChangshaChina
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9
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Lilly AC, Astsaturov I, Golemis EA. Intrapancreatic fat, pancreatitis, and pancreatic cancer. Cell Mol Life Sci 2023; 80:206. [PMID: 37452870 PMCID: PMC10349727 DOI: 10.1007/s00018-023-04855-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 06/29/2023] [Accepted: 07/03/2023] [Indexed: 07/18/2023]
Abstract
Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of pancreatic cancer is gradually increasing, linked to an aging population and increasing rates of obesity and pancreatitis, which are risk factors for this cancer. Sources of risk include adipokine signaling from fat cells throughout the body, elevated levels of intrapancreatic intrapancreatic adipocytes (IPAs), inflammatory signals arising from pancreas-infiltrating immune cells and a fibrotic environment induced by recurring cycles of pancreatic obstruction and acinar cell lysis. Once cancers become established, reorganization of pancreatic tissue typically excludes IPAs from the tumor microenvironment, which instead consists of cancer cells embedded in a specialized microenvironment derived from cancer-associated fibroblasts (CAFs). While cancer cell interactions with CAFs and immune cells have been the topic of much investigation, mechanistic studies of the source and function of IPAs in the pre-cancerous niche are much less developed. Intriguingly, an extensive review of studies addressing the accumulation and activity of IPAs in the pancreas reveals that unexpectedly diverse group of factors cause replacement of acinar tissue with IPAs, particularly in the mouse models that are essential tools for research into pancreatic cancer. Genes implicated in regulation of IPA accumulation include KRAS, MYC, TGF-β, periostin, HNF1, and regulators of ductal ciliation and ER stress, among others. These findings emphasize the importance of studying pancreas-damaging factors in the pre-cancerous environment, and have significant implications for the interpretation of data from mouse models for pancreatic cancer.
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Affiliation(s)
- Anna C Lilly
- Program in Cancer Signaling and Microenvironment, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA, 19111, USA
- Molecular & Cell Biology & Genetics (MCBG) Program, Drexel University College of Medicine, Philadelphia, PA, 19102, USA
| | - Igor Astsaturov
- Program in Cancer Signaling and Microenvironment, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA, 19111, USA
- The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Erica A Golemis
- Program in Cancer Signaling and Microenvironment, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA, 19111, USA.
- Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA.
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10
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ONO N, HORIKOSHI J, IZAWA T, NISHIYAMA K, TANAKA M, KUWAMURA M, AZUMA YT. L-arginine-induced pancreatitis aggravated by inhibiting Na +/Ca 2+ exchanger 1. J Vet Med Sci 2023; 85:657-666. [PMID: 37100607 PMCID: PMC10315542 DOI: 10.1292/jvms.22-0569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/12/2023] [Indexed: 04/28/2023] Open
Abstract
Na+/Ca2+ exchangers (NCX) are an exchange transporter of Na+ and Ca2+ ions on the plasma membrane. There are three types of NCX: NCX1, NCX2, and NCX3. We have been working for many years to understand the role of NCX1 and NCX2 in gastrointestinal motility. In this study, we focused on the pancreas, an organ closely related to the gastrointestinal tract, and used a mouse model of acute pancreatitis to investigate a possible role for NCX1 in the pathogenesis of pancreatitis. We characterized a model of acute pancreatitis induced by excessive doses of L-arginine. We administered the NCX1 inhibitor SEA0400 (1 mg/kg) 1 hr prior to L-arginine-induced pancreatitis and evaluated pathological changes. Mice treated with NCX1 inhibitors show exacerbation of the disease with decreased survival and increased amylase activity in response to L-arginine-induced experimental acute pancreatitis, and this exacerbation correlates with increased autophagy mediated by LC3B and p62. These results suggest that NCX1 has a role in regulating pancreatic inflammation and acinar cell homeostasis.
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Affiliation(s)
- Naoshige ONO
- Laboratory of Prophylactic Pharmacology, Osaka Metropolitan
University Graduate School of Veterinary Science, Osaka, Japan
| | - Joji HORIKOSHI
- Laboratory of Prophylactic Pharmacology, Osaka Metropolitan
University Graduate School of Veterinary Science, Osaka, Japan
| | - Takeshi IZAWA
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University Graduate School of Veterinary Science, Osaka, Japan
| | - Kazuhiro NISHIYAMA
- Laboratory of Prophylactic Pharmacology, Osaka Metropolitan
University Graduate School of Veterinary Science, Osaka, Japan
| | - Miyuu TANAKA
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University Graduate School of Veterinary Science, Osaka, Japan
| | - Mitsuru KUWAMURA
- Laboratory of Veterinary Pathology, Osaka Metropolitan
University Graduate School of Veterinary Science, Osaka, Japan
| | - Yasu-Taka AZUMA
- Laboratory of Prophylactic Pharmacology, Osaka Metropolitan
University Graduate School of Veterinary Science, Osaka, Japan
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11
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Marstrand-Daucé L, Lorenzo D, Chassac A, Nicole P, Couvelard A, Haumaitre C. Acinar-to-Ductal Metaplasia (ADM): On the Road to Pancreatic Intraepithelial Neoplasia (PanIN) and Pancreatic Cancer. Int J Mol Sci 2023; 24:9946. [PMID: 37373094 PMCID: PMC10298625 DOI: 10.3390/ijms24129946] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Adult pancreatic acinar cells show high plasticity allowing them to change in their differentiation commitment. Pancreatic acinar-to-ductal metaplasia (ADM) is a cellular process in which the differentiated pancreatic acinar cells transform into duct-like cells. This process can occur as a result of cellular injury or inflammation in the pancreas. While ADM is a reversible process allowing pancreatic acinar regeneration, persistent inflammation or injury can lead to the development of pancreatic intraepithelial neoplasia (PanIN), which is a common precancerous lesion that precedes pancreatic ductal adenocarcinoma (PDAC). Several factors can contribute to the development of ADM and PanIN, including environmental factors such as obesity, chronic inflammation and genetic mutations. ADM is driven by extrinsic and intrinsic signaling. Here, we review the current knowledge on the cellular and molecular biology of ADM. Understanding the cellular and molecular mechanisms underlying ADM is critical for the development of new therapeutic strategies for pancreatitis and PDAC. Identifying the intermediate states and key molecules that regulate ADM initiation, maintenance and progression may help the development of novel preventive strategies for PDAC.
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Affiliation(s)
- Louis Marstrand-Daucé
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
| | - Diane Lorenzo
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
| | - Anaïs Chassac
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
- Department of Pathology, Bichat Hospital, Université Paris Cité, 75018 Paris, France
| | - Pascal Nicole
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
| | - Anne Couvelard
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
- Department of Pathology, Bichat Hospital, Université Paris Cité, 75018 Paris, France
| | - Cécile Haumaitre
- INSERM UMR1149, Inflammation Research Center (CRI), Université Paris Cité, 75018 Paris, France; (L.M.-D.); (D.L.); (A.C.); (P.N.); (A.C.)
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12
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An J, Jiang T, Qi L, Xie K. Acinar cells and the development of pancreatic fibrosis. Cytokine Growth Factor Rev 2023; 71-72:40-53. [PMID: 37291030 DOI: 10.1016/j.cytogfr.2023.05.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/10/2023]
Abstract
Pancreatic fibrosis is caused by excessive deposition of extracellular matrixes of collagen and fibronectin in the pancreatic tissue as a result of repeated injury often seen in patients with chronic pancreatic diseases. The most common causative conditions include inborn errors of metabolism, chemical toxicity and autoimmune disorders. Its pathophysiology is highly complex, including acinar cell injury, acinar stress response, duct dysfunction, pancreatic stellate cell activation, and persistent inflammatory response. However, the specific mechanism remains to be fully clarified. Although the current therapeutic strategies targeting pancreatic stellate cells show good efficacy in cell culture and animal models, they are not satisfactory in the clinic. Without effective intervention, pancreatic fibrosis can promote the transformation from pancreatitis to pancreatic cancer, one of the most lethal malignancies. In the normal pancreas, the acinar component accounts for 82% of the exocrine tissue. Abnormal acinar cells may activate pancreatic stellate cells directly as cellular source of fibrosis or indirectly via releasing various substances and initiate pancreatic fibrosis. A comprehensive understanding of the role of acinar cells in pancreatic fibrosis is critical for designing effective intervention strategies. In this review, we focus on the role of and mechanisms underlying pancreatic acinar injury in pancreatic fibrosis and their potential clinical significance.
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Affiliation(s)
- Jianhong An
- SCUT-QMPH Joint Laboratory for Pancreatic Cancer Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong 511518, China; Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China
| | - Tingting Jiang
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China
| | - Ling Qi
- SCUT-QMPH Joint Laboratory for Pancreatic Cancer Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong 511518, China.
| | - Keping Xie
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China.
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13
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Vianello C, Salluzzo M, Anni D, Boriero D, Buffelli M, Carboni L. Increased Expression of Autophagy-Related Genes in Alzheimer's Disease-Type 2 Diabetes Mellitus Comorbidity Models in Cells. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:ijerph20054540. [PMID: 36901549 PMCID: PMC10002426 DOI: 10.3390/ijerph20054540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 05/31/2023]
Abstract
The association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) has been extensively demonstrated, but despite this, the pathophysiological mechanisms underlying it are still unknown. In previous work, we discovered a central role for the autophagy pathway in the common alterations observed between AD and T2DM. In this study, we further investigate the role of genes belonging to this pathway, measuring their mRNA expression and protein levels in 3xTg-AD transgenic mice, an animal model of AD. Moreover, primary mouse cortical neurons derived from this model and the human H4Swe cell line were used as cellular models of insulin resistance in AD brains. Hippocampal mRNA expression showed significantly different levels for Atg16L1, Atg16L2, GabarapL1, GabarapL2, and Sqstm1 genes at different ages of 3xTg-AD mice. Significantly elevated expression of Atg16L1, Atg16L2, and GabarapL1 was also observed in H4Swe cell cultures, in the presence of insulin resistance. Gene expression analysis confirmed that Atg16L1 was significantly increased in cultures from transgenic mice when insulin resistance was induced. Taken together, these results emphasise the association of the autophagy pathway in AD-T2DM co-morbidity, providing new evidence about the pathophysiology of both diseases and their mutual interaction.
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Affiliation(s)
- Clara Vianello
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
| | - Marco Salluzzo
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
| | - Daniela Anni
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy
| | - Diana Boriero
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy
| | - Mario Buffelli
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie, 8, 37134 Verona, Italy
| | - Lucia Carboni
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
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14
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Abstract
Macroautophagy/autophagy, a fundamental cell process for nutrient recycling and defense against pathogens (termed xenophagy), is crucial to human health. ATG16L2 (autophagy related 16 like 2) is an autophagic protein and a paralog of ATG16L1. Both proteins are implicated in similar diseases such as cancer and other chronic diseases; however, most autophagy studies to date have primarily focused on the function of ATG16L1, with ATG16L2 remaining uncharacterized and understudied. Overexpression of ATG16L2 has been reported in various cancers including colorectal, gastric, and prostate carcinomas, whereas altered methylation of ATG16L2 has been associated with lung cancer formation and poorer response to therapy in leukemia. In addition, ATG16L2 polymorphisms have been implicated in a range of other diseases including inflammatory bowel diseases and neurodegenerative disorders. Despite this likely role in human health, the function of this enigmatic protein in autophagy remains unknown. Here, we review current studies on ATG16L2 and collate evidence that suggests that this protein is a potential modulator of autophagy as well as the implications this has on pathogenesis.Abbreviations: ATG5: autophagy related 5; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; ATG16L2: autophagy related 16 like 2; CD: Crohn disease; IBD: inflammatory bowel diseases; IRGM: immunity related GTPase M; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PE: phosphatidylethanolamine; RB1CC1: RB1 inducible coiled-coil 1; SLE: systemic lupus erythematosus; WIPI2B: WD repeat domain, phosphoinositide interacting 2B.
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Affiliation(s)
- Laurence Don Wai Luu
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia,CONTACT Laurence Don Wai Luu School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Nadeem O. Kaakoush
- School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Natalia Castaño-Rodríguez
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia,Natalia Castaño-Rodríguez School of Biotechnology and Biomolecular Sciences, Faculty of Science, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
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15
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Pandol SJ, Gottlieb RA. Calcium, mitochondria and the initiation of acute pancreatitis. Pancreatology 2022; 22:838-845. [PMID: 35941013 DOI: 10.1016/j.pan.2022.07.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 07/16/2022] [Accepted: 07/19/2022] [Indexed: 12/11/2022]
Abstract
Acute pancreatitis is characterized by necrosis of its parenchymal cells and influx and activation of inflammatory cells that further promote injury and necrosis. This review is intended to discuss the central role of disorders of calcium metabolism and mitochondrial dysfunction in the mechanism of pancreatitis development. The disorders are placed in context of calcium and mitochondria in physiologic function of the pancreas. Moreover, we discuss potential therapeutics for preventing pathologic calcium signals that injure mitochondria and interventions that promote the removal of injured mitochondria and regenerate new and heathy populations of mitochondria.
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Affiliation(s)
- Stephen J Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
| | - Roberta A Gottlieb
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
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16
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Wang S, Chao X, Jiang X, Wang T, Rodriguez Y, Yang L, Pacher P, Ni HM, Ding WX. Loss of acinar cell VMP1 triggers spontaneous pancreatitis in mice. Autophagy 2022; 18:1572-1582. [PMID: 34709991 PMCID: PMC9298442 DOI: 10.1080/15548627.2021.1990672] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/30/2021] [Accepted: 10/04/2021] [Indexed: 12/19/2022] Open
Abstract
The pathogenesis of pancreatitis has been linked to disruption of organelle homeostasis including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress. However, the direct impact of aberrant organelle function on pancreatitis initiation and progression is largely unknown. Recently an ER membrane protein, VMP1 (vacuole membrane protein 1), has been reported to play a crucial role in autophagosome formation. Notably, we found that VMP1 is downregulated in both human chronic pancreatitis (CP) and experimental mouse acute pancreatitis (AP). Pancreatic acinar cell-specific vmp1 deletion promotes inflammation, acinar-to-ductal metaplasia, and fibrosis in mice, sharing histological similarities with human CP. Mechanistically, loss of pancreatic VMP1 leads to defective autophagic degradation and ER stress as well as activation of the NFE2L2/Nrf2 pathway. Genetic ablation of NFE2L2 attenuated pancreatitis in VMP1-deficient mice. Our data highlight the importance of VMP1 in modulating an integrated organelle stress response and its functional role in maintaining pancreas homeostasis in the context of CP.Abbreviations: AMY: amylase; ADM: acinar-to-ductal metaplasia; AP: acute pancreatitis; CASP3: caspase 3; CP: chronic pancreatitis; DDIT3/CHOP: DNA damage inducible transcript 3; DKO, double knockout; ER: endoplasmic reticulum; GCLC: glutamate-cysteine ligase catalytic subunit; GCLM: glutamate-cysteine ligase modifier subunit; HSPA5/BIP: heat shock protein family A (Hsp70) member 5; KO: knockout; KRT19/CK19: keratin 19; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MPO: myeloperoxidase; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; ND: normal donor; NQO1: NAD(P)H quinone dehydrogenase 1; PCNA: proliferating cell nuclear antigen; RIPA: radio-immunoprecipitation; SQSTM1/p62: sequestosome 1; SOX9: SRY-box transcription factor 9; TAP: trypsinogen activation peptide; TFEB: transcription factor EB; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; UB: ubiquitin; VMP1: vacuole membrane protein 1; XBP1: X-box binding protein 1; YAP1, Yes1 associated transcriptional regulator; ZG: zymogen granule.
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Affiliation(s)
- Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Xiaoxiao Jiang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Tiantian Wang
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yssa Rodriguez
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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17
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Functional IKK/NF-κB signaling in pancreatic stellate cells is essential to prevent autoimmune pancreatitis. Commun Biol 2022; 5:509. [PMID: 35624133 PMCID: PMC9142538 DOI: 10.1038/s42003-022-03371-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 04/14/2022] [Indexed: 01/07/2023] Open
Abstract
Pancreatic stellate cells (PSCs) are resident cells in the exocrine pancreas which contribute to pancreatic fibrogenesis and inflammation. Studies on NF-κB in pancreatitis so far focused mainly on the parenchymal and myeloid compartments. Here we show a protective immunomodulatory function of NF-κB in PSCs. Conditional deletion of NEMO (IKKγ) in PSCs leads to spontaneous pancreatitis with elevated circulating IgM, IgG and antinuclear autoantibodies (ANA) within 18 weeks. When further challenged with caerulein, NEMOΔCol1a2 mice show an exacerbated autoimmune phenotype characterized by increased infiltration of eosinophils, B and T lymphocytes with reduced latency period. Transcriptomic profiling shows that NEMOΔCol1a2 mice display molecular signatures resembling autoimmune pancreatitis patients. Mechanistically, we show that PSCΔNEMO cells produce high levels of CCL24 ex vivo which contributes to eosinophil recruitment, as neutralization with a CCL24 antibody abolishes the transwell migration of eosinophils. Our findings uncover an unexpected immunomodulatory role specifically of NF-κB in PSCs during pancreatitis. A model of autoimmune pancreatitis is developed by blocking the activation of NF-κB in pancreatic stellate cells, via conditional deletion of NEMO (IKKγ), which presents strong pancreatic inflammation with eosinophilia after the induction of chronic pancreatitis by repeated caerulein challenges.
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18
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p62 Promotes Survival and Hepatocarcinogenesis in Mice with Liver-Specific NEMO Ablation. Cancers (Basel) 2022; 14:cancers14102436. [PMID: 35626041 PMCID: PMC9139637 DOI: 10.3390/cancers14102436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Chronic liver injury is a predisposing factor for hepatocellular carcinoma (HCC) development. p62-mediated Nrf2 overactivation has been shown to drive liver injury and HCC in mice with hepatic impairment of autophagy. Here, we addressed the role of this pathway in a liver disease mouse model that does not exhibit inherent autophagy defect. Genetically-induced Nrf2 overactivation without concomitant strong increase in p62 expression did not aggravate liver injury and hepatocarcinogenesis. In contrast, p62-driven Nrf2 overactivation was prominent in liver tumors of mice that expressed a p62 mutant and showed enhanced hepatocarcinogenesis. Moreover, a negative correlation was observed between p62/Nrf2high liver tumors and the autophagosome marker LC3, suggesting that acquired autophagy defects precede the activation of this pro-tumorigenic pathway. Our results suggest that autophagy activators or Nrf2 inhibitors could be considered therapeutically in cases of p62/Nrf2high liver tumors. Abstract SQSTM1/p62 is a multitasking protein that functions as an autophagy receptor, but also as a signaling hub regulating diverse cellular pathways. p62 accumulation in mice with autophagy-deficient hepatocytes mediates liver damage and hepatocarcinogenesis through Nrf2 overactivation, yet the role of the p62-Keap1-Nrf2 axis in cell death and hepatocarcinogenesis in the absence of underlying autophagy defects is less clear. Here, we addressed the role of p62 and Nrf2 activation in a chronic liver disease model, namely mice with liver parenchymal cell-specific knockout of NEMO (NEMOLPC-KO), in which we demonstrate that they show no inherent autophagy impairment. Unexpectedly, systemic p62 ablation aggravated the phenotype and caused early postnatal lethality in NEMOLPC-KO mice. Expression of a p62 mutant (p62ΔEx2-5), which retains the ability to form aggregates and activate Nrf2 signaling, did not cause early lethality, but exacerbated hepatocarcinogenesis in these mice. Our immunohistological and molecular analyses showed that the increased tumor burden was only consistent with increased expression/stability of p62ΔEx2-5 driving Nrf2 hyperactivation, but not with other protumorigenic functions of p62, such as mTOR activation, cMYC upregulation or increased fibrosis. Surprisingly, forced activation of Nrf2 per se did not increase liver injury or tumor burden in NEMOLPC-KO mice, suggesting that autophagy impairment is a necessary prerequisite to unleash the Nrf2 oncogenic potential in mice with autophagy-competent hepatocytes.
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19
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Wang D, Yuan T, Liu J, Wen Z, Shen Y, Tang J, Wang Z, Wu X. ATG16L2 inhibits NLRP3 inflammasome activation through promoting ATG5‐12‐16L1 complex assembly and autophagy. Eur J Immunol 2022; 52:1321-1334. [PMID: 35426127 DOI: 10.1002/eji.202149764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 03/24/2022] [Accepted: 04/13/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Dongyang Wang
- Department of Gastrointestinal Surgery Renji Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai 200025 China
| | - Tianli Yuan
- Department of Gastrointestinal Surgery Renji Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai 200025 China
| | - Jiamin Liu
- Hongqiao International Institute of Medicine Shanghai Tongren Hospital/Faculty of Basic Medicine Shanghai Institute of Immunology Department of Immunology and Microbiology Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education Shanghai Jiao Tong University School of Medicine Shanghai 200025 China
| | - Zhoujin Wen
- Department of Gastrointestinal Surgery Renji Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai 200025 China
| | - Yuguang Shen
- Department of Gastrointestinal Surgery Renji Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai 200025 China
| | - Jian Tang
- Department of Gastrointestinal Surgery Renji Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai 200025 China
| | - Zheng Wang
- Department of Gastrointestinal Surgery Renji Hospital Affiliated Shanghai Jiao Tong University School of Medicine Shanghai 200025 China
| | - Xuefeng Wu
- Hongqiao International Institute of Medicine Shanghai Tongren Hospital/Faculty of Basic Medicine Shanghai Institute of Immunology Department of Immunology and Microbiology Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education Shanghai Jiao Tong University School of Medicine Shanghai 200025 China
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20
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IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines. Proc Natl Acad Sci U S A 2022; 119:2120956119. [PMID: 35121655 PMCID: PMC8833198 DOI: 10.1073/pnas.2120956119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/23/2021] [Indexed: 11/18/2022] Open
Abstract
The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus, coding for IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKα expression affects the TME. Here, we report that low IKKα expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cell (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1, CCL22, TNF, and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/c-Rel signaling cascade that stimulates Treg generation, these cytokines promote lung ADC progression. Depletion of TNFR2, c-Rel, or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion, reduced cancer cell IKKα activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC.
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21
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Zhang Z, Costa M. p62 functions as a signal hub in metal carcinogenesis. Semin Cancer Biol 2021; 76:267-278. [PMID: 33894381 PMCID: PMC9161642 DOI: 10.1016/j.semcancer.2021.04.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 04/06/2021] [Accepted: 04/15/2021] [Indexed: 12/13/2022]
Abstract
A number of metals are toxic and carcinogenic to humans. Reactive oxygen species (ROS) play an important role in metal carcinogenesis. Oxidative stress acts as the converging point among various stressors with ROS being the main intracellular signal transducer. In metal-transformed cells, persistent expression of p62 and erythroid 2-related factor 2 (Nrf2) result in apoptosis resistance, angiogenesis, inflammatory microenvironment, and metabolic reprogramming, contributing to overall mechanism of metal carcinogenesis. Autophagy, a conserved intracellular process, maintains cellular homeostasis by facilitating the turnover of protein aggregates, cellular debris, and damaged organelles. In addition to being a substrate of autophagy, p62 is also a crucial molecule in a myriad of cellular functions and in molecular events, which include oxidative stress, inflammation, apoptosis, cell proliferation, metabolic reprogramming, that modulate cell survival and tumor growth. The multiple functions of p62 are appreciated by its ability to interact with several key components involved in various oncogenic pathways. This review summarizes the current knowledge and progress in studies of p62 and metal carcinogenesis with emphasis on oncogenic pathways related to oxidative stress, inflammation, apoptosis, and metabolic reprogramming.
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Affiliation(s)
- Zhuo Zhang
- Department of Environmental Medicine, NYU School of Medicine, 341 East 25th Street, New York, NY 10010, USA
| | - Max Costa
- Department of Environmental Medicine, NYU School of Medicine, 341 East 25th Street, New York, NY 10010, USA.
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22
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Shu S, Wang H, Zhu J, Liu Z, Yang D, Wu W, Cai J, Chen A, Tang C, Dong Z. Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis. Cell Death Dis 2021; 12:1016. [PMID: 34716302 PMCID: PMC8556380 DOI: 10.1038/s41419-021-04274-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023]
Abstract
Both endoplasmic reticulum (ER) stress and autophagy have been implicated in chronic kidney injury and renal fibrosis. However, the relationship and regulatory mechanisms between ER stress and autophagy under this condition remain largely unknown. In this study, we first established a mouse model of ER stress-induced chronic kidney injury by 2 weekly injections of a low dose of tunicamycin (TM), a classical ER stress inducer. This model showed the induction of ER stress, autophagy, fibrosis and apoptosis in kidney tissues. In vitro, TM also induced ER stress, autophagy, fibrosis and apoptosis in HK-2 human kidney proximal tubular cells and BUMPT-306 mouse kidney proximal tubular cells. In these cells, autophagy inhibitor suppressed TM-induced fibrotic changes and apoptosis, suggesting an involvement of autophagy in ER stress-associated chronic kidney injury. PERK inhibitor ameliorated autophagy, fibrotic protein expression and apoptosis in TM-treated cells, indicating a role of the PERK/eIF2α pathway in autophagy activation during ER stress. Similar results were shown in TGF-β1-treated HK-2 cells. Interestingly, in both TM- or TGF-β1-treated kidney proximal tubular cells, inhibition of autophagy exaggerated ER stress, suggesting that autophagy induced by ER stress provides a negative feedback mechanism to reduce the stress. Together, these results unveil a reciprocal regulation between ER stress and autophagy in chronic kidney injury and fibrosis.
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Affiliation(s)
- Shaoqun Shu
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Hui Wang
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Jiefu Zhu
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Zhiwen Liu
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Danyi Yang
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Wenwen Wu
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Juan Cai
- grid.452708.c0000 0004 1803 0208Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011 China
| | - Anqun Chen
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011, China.
| | - Chengyuan Tang
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011, China.
| | - Zheng Dong
- Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital at Central South University, Changsha, 410011, China. .,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.
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23
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Huang X, Glessner JT, Huang J, Zhou D, March ME, Wang H, Xia Q, Hakonarson H, Li J. Discovery of Novel Host Molecular Factors Underlying HBV/HCV Infection. Front Cell Dev Biol 2021; 9:690882. [PMID: 34458256 PMCID: PMC8397444 DOI: 10.3389/fcell.2021.690882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 07/06/2021] [Indexed: 11/13/2022] Open
Abstract
Hepatitis is an inflammatory condition of the liver, which is frequently caused by the infection of hepatitis B virus (HBV) or hepatitis C virus (HCV). Hepatitis can lead to the development of chronic complications including cancer, making it a major public health burden. Co-infection of HBV and HCV can result in faster disease progression. Therefore, it is important to identify shared genetic susceptibility loci for HBV and HCV infection to further understand the underlying mechanism. Through a meta-analysis based on genome-wide association summary statistics of HBV and HCV infection, we found one novel locus in the Asian population and two novel loci in the European population. By functional annotation based on multi-omics data, we identified the likely target genes at each novel locus, such as HMGB1 and ATF3, which play a critical role in autophagy and immune response to virus. By re-analyzing a microarray dataset from Hmgb1–/– mice and RNA-seq data from mouse liver tissue overexpressing ATF3, we found that differential expression of autophagy and immune and metabolic gene pathways underlie these conditions. Our study reveals novel common susceptibility loci to HBV and HCV infection, supporting their role in linking autophagy signaling and immune response.
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Affiliation(s)
- Xubo Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Joseph T Glessner
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jinxia Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Desheng Zhou
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Michael E March
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Hongna Wang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Qianghua Xia
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Division of Human Genetics and Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jin Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China.,Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes, Guangzhou Medical University, Guangzhou, China
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24
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Mareninova OA, Vegh ET, Shalbueva N, Wightman CJ, Dillon DL, Malla S, Xie Y, Takahashi T, Rakonczay Z, French SW, Gaisano HY, Gorelick FS, Pandol SJ, Bensinger SJ, Davidson NO, Dawson DW, Gukovsky I, Gukovskaya AS. Dysregulation of mannose-6-phosphate-dependent cholesterol homeostasis in acinar cells mediates pancreatitis. J Clin Invest 2021; 131:146870. [PMID: 34128834 PMCID: PMC8321573 DOI: 10.1172/jci146870] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 06/11/2021] [Indexed: 01/18/2023] Open
Abstract
Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that the mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene encoding a key enzyme in the M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of nonesterified cholesterol in lysosomes/autolysosomes, its depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab-/- and experimental models involve a disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab-/- liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab-/- mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of the M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.
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Affiliation(s)
- Olga A. Mareninova
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Eszter T. Vegh
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Natalia Shalbueva
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Carli J.M. Wightman
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Dustin L. Dillon
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Sudarshan Malla
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Yan Xie
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | | | - Zoltan Rakonczay
- Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | - Samuel W. French
- Department of Pathology, Harbor-UCLA Medical Center, Torrance, California, USA
| | | | - Fred S. Gorelick
- Departments of Cell Biology and Internal Medicine, Yale University School of Medicine and VA West Haven, West Haven, Connecticut, USA
| | - Stephen J. Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | | | - Nicholas O. Davidson
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - David W. Dawson
- Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Ilya Gukovsky
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
| | - Anna S. Gukovskaya
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, California, USA
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25
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Mandhair HK, Novak U, Radpour R. Epigenetic regulation of autophagy: A key modification in cancer cells and cancer stem cells. World J Stem Cells 2021; 13:542-567. [PMID: 34249227 PMCID: PMC8246247 DOI: 10.4252/wjsc.v13.i6.542] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/02/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic alterations play a decisive role in cancer initiation and propagation via the regulation of key tumor suppressor genes and oncogenes or by modulation of essential signaling pathways. Autophagy is a highly regulated mechanism required for the recycling and degradation of surplus and damaged cytoplasmic constituents in a lysosome dependent manner. In cancer, autophagy has a divergent role. For instance, autophagy elicits tumor promoting functions by facilitating metabolic adaption and plasticity in cancer stem cells (CSCs) and cancer cells. Moreover, autophagy exerts pro-survival mechanisms to these cancerous cells by influencing survival, dormancy, immunosurveillance, invasion, metastasis, and resistance to anti-cancer therapies. In addition, recent studies have demonstrated that various tumor suppressor genes and oncogenes involved in autophagy, are tightly regulated via different epigenetic modifications, such as DNA methylation, histone modifications and non-coding RNAs. The impact of epigenetic regulation of autophagy in cancer cells and CSCs is not well-understood. Therefore, uncovering the complex mechanism of epigenetic regulation of autophagy provides an opportunity to improve and discover novel cancer therapeutics. Subsequently, this would aid in improving clinical outcome for cancer patients. In this review, we provide a comprehensive overview of the existing knowledge available on epigenetic regulation of autophagy and its importance in the maintenance and homeostasis of CSCs and cancer cells.
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Affiliation(s)
- Harpreet K Mandhair
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Urban Novak
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
| | - Ramin Radpour
- Department for BioMedical Research, University of Bern, Bern 3008, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3008, Switzerland
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26
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Su H, Yang F, Fu R, Li X, French R, Mose E, Pu X, Trinh B, Kumar A, Liu J, Antonucci L, Todoric J, Liu Y, Hu Y, Diaz-Meco MT, Moscat J, Metallo CM, Lowy AM, Sun B, Karin M. Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis. Cancer Cell 2021; 39:678-693.e11. [PMID: 33740421 PMCID: PMC8119368 DOI: 10.1016/j.ccell.2021.02.016] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/17/2020] [Accepted: 02/19/2021] [Indexed: 12/29/2022]
Abstract
Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The autophagy to MP switch, which may be evolutionarily conserved and not cancer cell restricted, depends on activation of transcription factor NRF2 by the autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining autophagy and MP inhibitors in the clinic.
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Affiliation(s)
- Hua Su
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China
| | - Fei Yang
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China
| | - Rao Fu
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China
| | - Xin Li
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USA
| | - Randall French
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego Moores Cancer Center, La Jolla, CA 92093, USA
| | - Evangeline Mose
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego Moores Cancer Center, La Jolla, CA 92093, USA
| | - Xiaohong Pu
- Department of Pathology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China
| | - Brittney Trinh
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Avi Kumar
- Institute of Engineering in Medicine, Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Junlai Liu
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Laura Antonucci
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Jelena Todoric
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Laboratory Medicine, Medical University of Vienna, Vienna 1090, Austria
| | - Yuan Liu
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Yinling Hu
- Laboratory of Cancer ImmunoMetabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USA
| | - Maria T Diaz-Meco
- Department of Pathology and Laboratory Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Jorge Moscat
- Department of Pathology and Laboratory Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Christian M Metallo
- Institute of Engineering in Medicine, Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA 92093, USA
| | - Andrew M Lowy
- Department of Surgery, Division of Surgical Oncology, University of California, San Diego Moores Cancer Center, La Jolla, CA 92093, USA
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210000, China.
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
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27
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Iwama H, Mehanna S, Imasaka M, Hashidume S, Nishiura H, Yamamura KI, Suzuki C, Uchiyama Y, Hatano E, Ohmuraya M. Cathepsin B and D deficiency in the mouse pancreas induces impaired autophagy and chronic pancreatitis. Sci Rep 2021; 11:6596. [PMID: 33758261 PMCID: PMC7988038 DOI: 10.1038/s41598-021-85898-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 03/02/2021] [Indexed: 12/27/2022] Open
Abstract
The major lysosomal proteases, Cathepsin B (CTSB), Cathepsin D (CTSD) and Cathepsin L (CTSL), are implicated in autophagic activity. To investigate the role of each cathepsin in the exocrine pancreas, we generated mice in which the pancreas was specifically deficient in Ctsb, Ctsd and Ctsl. Each of these gene knockout (KO) and Ctsb;Ctsl and Ctsd;Ctsl double-knockout (DKO) mice were almost normal. However, we found cytoplasmic degeneration in the pancreatic acinar cells of Ctsb;Ctsd DKO mice, similar to autophagy related 5 (Atg5) KO mice. LC3 and p62 (autophagy markers) showed remarkable accumulation and the numbers of autophagosomes and autolysosomes were increased in the pancreatic acinar cells of Ctsb;Ctsd DKO mice. Moreover, these Ctsb;Ctsd DKO mice also developed chronic pancreatitis (CP). Thus, we conclude that both Ctsb and Ctsd deficiency caused impaired autophagy in the pancreatic acinar cells, and induced CP in mice.
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Affiliation(s)
- Hideaki Iwama
- Department of Genetics, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.,Department of Gastroenterological Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan
| | - Sally Mehanna
- Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.,Department of Veterinary Hygiene and Management, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
| | - Mai Imasaka
- Department of Genetics, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Shinsuke Hashidume
- Department of Genetics, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hiroshi Nishiura
- Division of Functional Pathology, Department of Pathology, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan
| | - Ken-Ichi Yamamura
- Institute of Resource Development and Analysis, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan
| | - Chigure Suzuki
- Department of Pharmacology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Yasuo Uchiyama
- Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Etsuro Hatano
- Department of Gastroenterological Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, 663-8501, Japan
| | - Masaki Ohmuraya
- Department of Genetics, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
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28
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Li X, Hu Y. Attribution of NF-κB Activity to CHUK/IKKα-Involved Carcinogenesis. Cancers (Basel) 2021; 13:cancers13061411. [PMID: 33808757 PMCID: PMC8003426 DOI: 10.3390/cancers13061411] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/08/2021] [Accepted: 03/15/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary CHUK/IKKα has emerged as a novel tumor suppressor in several organs of humans and mice. In general, activation of NF-κB promotes inflammation and tumorigenesis. IKKα reduction stimulates inflammatory responses including NF-κB’s targets and NF-κB-independent pathways for tumor promotion. Specific phenomena from genetically-modified mice and human TCGA database show the crosstalk between IKKα and NF-κB although their nature paths for normal organ development and the disease and cancer pathogenesis remains largely under investigation. In this review, we focus on the interplay between IKKα and NF-κB signaling during carcinogenesis. A better understanding of their relationship will provide insight into therapeutic targets of cancer. Abstract Studies analyzing human cancer genome sequences and genetically modified mouse models have extensively expanded our understanding of human tumorigenesis, even challenging or reversing the dogma of certain genes as originally characterized by in vitro studies. Inhibitor-κB kinase α (IKKα), which is encoded by the conserved helix-loop-helix ubiquitous kinase (CHUK) gene, is first identified as a serine/threonine protein kinase in the inhibitor-κB kinase complex (IKK), which is composed of IKKα, IKKβ, and IKKγ (NEMO). IKK phosphorylates serine residues 32 and 36 of IκBα, a nuclear factor-κB (NF-κB) inhibitor, to induce IκBα protein degradation, resulting in the nuclear translocation of NF-κB dimers that function as transcriptional factors to regulate immunity, infection, lymphoid organ/cell development, cell death/growth, and tumorigenesis. NF-κB and IKK are broadly and differentially expressed in the cells of our body. For a long time, the idea that the IKK complex acts as a direct upstream activator of NF-κB in carcinogenesis has been predominately accepted in the field. Surprisingly, IKKα has emerged as a novel suppressor for skin, lung, esophageal, and nasopharyngeal squamous cell carcinoma, as well as lung and pancreatic adenocarcinoma (ADC). Thus, Ikkα loss is a tumor driver in mice. On the other hand, lacking the RANKL/RANK/IKKα pathway impairs mammary gland development and attenuates oncogene- and chemical carcinogen-induced breast and prostate tumorigenesis and metastasis. In general, NF-κB activation leads one of the major inflammatory pathways and stimulates tumorigenesis. Since IKKα and NF-κB play significant roles in human health, revealing the interplay between them greatly benefits the diagnosis, treatment, and prevention of human cancer. In this review, we discuss the intriguing attribution of NF-κB to CHUK/IKKα-involved carcinogenesis.
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29
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Autophagy in Acute Pancreatitis: Organelle Interaction and microRNA Regulation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8811935. [PMID: 33628384 PMCID: PMC7884169 DOI: 10.1155/2021/8811935] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/23/2020] [Accepted: 01/07/2021] [Indexed: 12/16/2022]
Abstract
Acute pancreatitis (AP) is a common disorder with significant hospital admission and mortality. Due to the unclarified pathological mechanism, there is still no effective and specific treatment for AP. Recently, autophagy has been found to be closely related with occurrence and development of AP, which is crucial in determining its severity and outcomes. Emerging evidence indicates that autophagy can be regulated and influenced by microRNAs and organelles, including mitochondria, endoplasmic reticulum and lysosome, through various ways in AP. Of note, the complex interplays and close relationships among autophagy, microRNA and organelles in AP are vital for figuring out pathogenesis but not clear yet. Thus, this review summarizes the role of autophagy in the pathological mechanism of AP, especially the relationship between impaired autophagy and organelles, and discusses the regulatory mechanism of microRNA on autophagy, which could offer new insights into understanding the pathogenesis of AP and developing new potential therapeutic targets against AP.
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30
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Mareninova OA, Jia W, Gretler SR, Holthaus CL, Thomas DDH, Pimienta M, Dillon DL, Gukovskaya AS, Gukovsky I, Groblewski GE. Transgenic expression of GFP-LC3 perturbs autophagy in exocrine pancreas and acute pancreatitis responses in mice. Autophagy 2020; 16:2084-2097. [PMID: 31942816 PMCID: PMC7595606 DOI: 10.1080/15548627.2020.1715047] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 12/25/2019] [Accepted: 01/08/2020] [Indexed: 12/20/2022] Open
Abstract
Pancreatitis is a common, sometimes fatal, disease of exocrine pancreas, initiated by damaged acinar cells. Recent studies implicate disordered macroautophagy/autophagy in pancreatitis pathogenesis. ATG8/LC3 protein is critical for autophagosome formation and a widely used marker of autophagic vacuoles. Transgenic GFP-LC3 mice are a valuable tool to investigate autophagy ; however, comparison of homeostatic and disease responses between GFP-LC3 and wild-type (WT) mice has not been done. We examined the effects of GFP-LC3 expression on autophagy, acinar cell function, and experimental pancreatitis. Unexpectedly, GFP-LC3 expression markedly increased endogenous LC3-II level in pancreas, caused by downregulation of ATG4B, the protease that deconjugates/delipidates LC3-II. By contrast, GFP-LC3 expression had lesser or no effect on autophagy in liver, lung and spleen. Autophagic flux analysis showed that autophagosome formation in GFP-LC3 acinar cells increased 3-fold but was not fully counterbalanced by increased autophagic degradation. Acinar cell (ex vivo) pancreatitis inhibited autophagic flux in WT and essentially blocked it in GFP-LC3 cells. In vivo pancreatitis caused autophagy impairment in WT mice, manifest by upregulation of LC3-II and SQSTM1/p62, increased number and size of autophagic vacuoles, and decreased level of TFEB, all of which were exacerbated in GFP-LC3 mice. GFP-LC3 expression affected key pancreatitis responses; most dramatically, it worsened increases in serum AMY (amylase), a diagnostic marker of acute pancreatitis, in several mouse models. The results emphasize physiological importance of autophagy for acinar cell function, demonstrate organ-specific effects of GFP-LC3 expression, and indicate that application of GFP-LC3 mice in disease models should be done with caution.Abbreviations: AP: acute pancreatitis; Arg-AP: L-arginine-induced acute pancreatitis; ATG: autophagy-related (protein); AVs: autophagic vacuoles; CCK: cholecystokinin-8; CDE: choline-deficient, D,L-ethionine supplemented diet; CER: caerulein (ortholog of CCK); CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; ER: endoplasmic reticulum; LAMP: lysosomal-associated membrane protein; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; TEM: transmission electron microscopy; TFEB: transcription factor EB; ZG: zymogen granule(s).
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Affiliation(s)
- Olga A. Mareninova
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
- Pancreatic Research Group, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Wenzhuo Jia
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
- Department of General Surgery, Beijing Hospital, National Centre of Gerontology, Beijing, China
| | - Sophie R. Gretler
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
- Pancreatic Research Group, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Conner L. Holthaus
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI, USA
| | - Diana D. H. Thomas
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI, USA
| | - Michael Pimienta
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Dustin L. Dillon
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
- Pancreatic Research Group, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Anna S. Gukovskaya
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
- Pancreatic Research Group, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Ilya Gukovsky
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
- Pancreatic Research Group, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Guy E. Groblewski
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI, USA
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Sudhakar JN, Lu HH, Chiang HY, Suen CS, Hwang MJ, Wu SY, Shen CN, Chang YM, Li FA, Liu FT, Shui JW. Lumenal Galectin-9-Lamp2 interaction regulates lysosome and autophagy to prevent pathogenesis in the intestine and pancreas. Nat Commun 2020; 11:4286. [PMID: 32855403 PMCID: PMC7453023 DOI: 10.1038/s41467-020-18102-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 08/05/2020] [Indexed: 12/14/2022] Open
Abstract
Intracellular galectins are carbohydrate-binding proteins capable of sensing and repairing damaged lysosomes. As in the physiological conditions glycosylated moieties are mostly in the lysosomal lumen but not cytosol, it is unclear whether galectins reside in lysosomes, bind to glycosylated proteins, and regulate lysosome functions. Here, we show in gut epithelial cells, galectin-9 is enriched in lysosomes and predominantly binds to lysosome-associated membrane protein 2 (Lamp2) in a Asn(N)-glycan dependent manner. At the steady state, galectin-9 binding to glycosylated Asn175 of Lamp2 is essential for functionality of lysosomes and autophagy. Loss of N-glycan-binding capability of galectin-9 causes its complete depletion from lysosomes and defective autophagy, leading to increased endoplasmic reticulum (ER) stress preferentially in autophagy-active Paneth cells and acinar cells. Unresolved ER stress consequently causes cell degeneration or apoptosis that associates with colitis and pancreatic disorders in mice. Therefore, lysosomal galectins maintain homeostatic function of lysosomes to prevent organ pathogenesis.
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Affiliation(s)
| | - Hsueh-Han Lu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Hung-Yu Chiang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ching-Shu Suen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Ming-Jing Hwang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Sung-Yu Wu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chia-Ning Shen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Yao-Ming Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Fu-An Li
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Fu-Tong Liu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jr-Wen Shui
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
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Qian W, Xiao Q, Wang L, Qin T, Xiao Y, Li J, Yue Y, Zhou C, Duan W, Ma Q, Ma J. Resveratrol slows the tumourigenesis of pancreatic cancer by inhibiting NFκB activation. Biomed Pharmacother 2020; 127:110116. [PMID: 32428833 DOI: 10.1016/j.biopha.2020.110116] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 03/17/2020] [Accepted: 03/19/2020] [Indexed: 02/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumour with an extremely poor prognosis due to its insidious initiation and a lack of therapeutic strategies. Resveratrol suppresses pancreatic cancer progression and attenuates pancreatitis by modulating multiple targets, including nuclear factor kappa B (NFκB) signalling pathways. However, the effect of resveratrol on pancreatic cancer initiation and its mechanisms remain unclear. In this study, we utilised the LSL-KrasG12D/+; Pdx1-Cre (KC) spontaneous pancreatic precancerous lesion mouse model to explore the anti-tumourigenesis mechanisms of resveratrol in vivo. In vitro acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasias (PanINs) formation assays were performed by pancreatic acinar cell 3-dimensional (3D) culture. Histopathological analysis was used to examine the pathological morphology of pancreatic tissues. Resveratrol prevented the progression of pancreatic precancerous lesions and inhibited the activation of NFκB signalling pathway-related molecules in KC mouse pancreatic tissues. In addition, resveratrol reduced the severity of cerulein-induced pancreatitis and the formation of ADM/PanINs in vivo and in vitro, which may be related to its effect on NFκB inactivation. Furthermore, pancreatic acinar 3D culture demonstrated that activation of the NFκB signalling pathway promoted the formation of ADM/PanINs in vitro, and this initiating effect of NFκB was blocked by resveratrol. Resveratrol slowed the tumourigenesis of pancreatic cancer by inhibiting NFκB activation.
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Affiliation(s)
- Weikun Qian
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Qigui Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Lin Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Tao Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Ying Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Jie Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Yangyang Yue
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Cancan Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Wanxing Duan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Jiguang Ma
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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Takahashi T, Miao Y, Kang F, Dolai S, Gaisano HY. Susceptibility Factors and Cellular Mechanisms Underlying Alcoholic Pancreatitis. Alcohol Clin Exp Res 2020; 44:777-789. [PMID: 32056245 DOI: 10.1111/acer.14304] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/03/2020] [Indexed: 12/16/2022]
Abstract
Alcohol is a major cause of acute and chronic pancreatitis. There have been some recent advances in the understanding of the mechanisms underlying alcoholic pancreatitis, which include perturbation in mitochondrial function and autophagy and ectopic exocytosis, with some of these cellular events involving membrane fusion soluble N-ethylmaleimide-sensitive factor receptor protein receptor proteins. Although new insights have been unraveled recently, the precise mechanisms remain complex, and their finer details have yet to be established. The overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also the stellate cells and duct cells. Why only some are more susceptible to pancreatitis and with increased severity, while others are not, would suggest that there may be undefined protective factors or mechanisms that enhance recovery and regeneration after injury. Furthermore, there are confounding influences of lifestyle factors such as smoking and diet, and genetic background. Whereas alcohol and smoking cessation and a generally healthy lifestyle are intuitively the advice given to these patients afflicted with alcoholic pancreatitis in order to reduce disease recurrence and progression, there is as yet no specific treatment. A more complete understanding of the pathogenesis of pancreatitis from which novel therapeutic targets could be identified will have a great impact, particularly with the stubbornly high fatality (>30%) of severe pancreatitis. This review focuses on the susceptibility factors and underlying cellular mechanisms of alcohol injury on the exocrine pancreas.
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Affiliation(s)
- Toshimasa Takahashi
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Yifan Miao
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Fei Kang
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Subhankar Dolai
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Herbert Y Gaisano
- From the, Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
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34
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Zhang X, Chu J, Sun H, Zhao D, Ma B, Xue D, Zhang W, Li Z. MiR-155 aggravates impaired autophagy of pancreatic acinar cells through targeting Rictor. Acta Biochim Biophys Sin (Shanghai) 2020; 52:192-199. [PMID: 31942966 DOI: 10.1093/abbs/gmz152] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 02/06/2023] Open
Abstract
The aim of this study was to investigate the role and mechanism of miR-155 in regulating autophagy in a caerulein-induced acute pancreatitis (AP) cellular model. GFP-LC3 immunofluorescence assay was performed to detect autophagy vesicle formation in pancreatic acinar cell line AR42J. AR42J cells were transfected with miR-155 mimic, inhibitor, and corresponding controls to explore the effect of miR-155 on autophagy. The protein levels of LC3-I, LC3-II, Beclin-1, and p62 were analyzed by western blot analysis. Dual-luciferase reporter assay was performed to verify the interaction between miR-155 and Rictor (RPTOR independent companion of MTOR complex 2). The results showed that caerulein treatment induced impaired autophagy as evidenced by an increase in the accumulation of p62 together with LC3-II in AR42J cells, accompanied by miR-155 upregulation. Furthermore, miR-155 overexpression aggravated, whereas miR-155 silencing reduced the caerulein-induced impairment of autophagy. Mechanistically, Rictor was confirmed to be a direct target of miR-155, which could rescue the miR-155 overexpression-mediated aggravation of impaired autophagy. Collectively, these findings indicate that miR-155 aggravates impaired autophagy in caerulein-treated pancreatic acinar cells by targeting Rictor.
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Affiliation(s)
- Xueming Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Jiangtao Chu
- Department of Endoscopy, National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Haijun Sun
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Dali Zhao
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Biao Ma
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Dongbo Xue
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Weihui Zhang
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
| | - Zhituo Li
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
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Chavdoula E, Habiel DM, Roupakia E, Markopoulos GS, Vasilaki E, Kokkalis A, Polyzos AP, Boleti H, Thanos D, Klinakis A, Kolettas E, Marcu KB. CHUK/IKK-α loss in lung epithelial cells enhances NSCLC growth associated with HIF up-regulation. Life Sci Alliance 2019; 2:2/6/e201900460. [PMID: 31792060 PMCID: PMC6892436 DOI: 10.26508/lsa.201900460] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 11/18/2019] [Accepted: 11/19/2019] [Indexed: 02/06/2023] Open
Abstract
IKKα is an NSCLC suppressor and its loss in mouse AT-II lung epithelial cells or in human NSCLC lines increased urethane-induced adenoma growth and xenograft burdens, respectively. IKKα loss can up-regulate HIF-1α, enhancing tumor growth under hypoxia. Through the progressive accumulation of genetic and epigenetic alterations in cellular physiology, non–small-cell lung cancer (NSCLC) evolves in distinct steps involving mutually exclusive oncogenic mutations in K-Ras or EGFR along with inactivating mutations in the p53 tumor suppressor. Herein, we show two independent in vivo lung cancer models in which CHUK/IKK-α acts as a major NSCLC tumor suppressor. In a novel transgenic mouse strain, wherein IKKα ablation is induced by tamoxifen (Tmx) solely in alveolar type II (AT-II) lung epithelial cells, IKKα loss increases the number and size of lung adenomas in response to the chemical carcinogen urethane, whereas IKK-β instead acts as a tumor promoter in this same context. IKKα knockdown in three independent human NSCLC lines (independent of K-Ras or p53 status) enhances their growth as tumor xenografts in immune-compromised mice. Bioinformatics analysis of whole transcriptome profiling followed by quantitative protein and targeted gene expression validation experiments reveals that IKKα loss can result in the up-regulation of activated HIF-1-α protein to enhance NSCLC tumor growth under hypoxic conditions in vivo.
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Affiliation(s)
- Evangelia Chavdoula
- Biomedical Research Foundation Academy of Athens, Athens, Greece.,Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece.,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece
| | | | - Eugenia Roupakia
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece.,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece
| | - Georgios S Markopoulos
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece.,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece
| | - Eleni Vasilaki
- Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Antonis Kokkalis
- Biomedical Research Foundation Academy of Athens, Athens, Greece
| | | | - Haralabia Boleti
- Intracellular Parasitism Laboratory, Department of Microbiology and Light Microscopy Unit, Hellenic Pasteur Institute, Athens, Greece
| | - Dimitris Thanos
- Biomedical Research Foundation Academy of Athens, Athens, Greece
| | | | - Evangelos Kolettas
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece .,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece
| | - Kenneth B Marcu
- Biomedical Research Foundation Academy of Athens, Athens, Greece .,Laboratory of Biology, School of Medicine, Faculty of Health Sciences, University of Ioannina, University Campus, Ioannina, Greece.,Biomedical Research Division, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Ioannina, Greece.,Departments of Biochemistry and Cell Biology and Pathology, Stony Brook University, Stony Brook, NY, USA.,Department of Biological Sciences, San Diego State University, San Diego, CA, USA
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Dong K, Chen X, Xie L, Yu L, Shen M, Wang Y, Wu S, Wang J, Lu J, Wei G, Xu D, Yang L. Spautin-A41 Attenuates Cerulein-Induced Acute Pancreatitis through Inhibition of Dysregulated Autophagy. Biol Pharm Bull 2019; 42:1789-1798. [DOI: 10.1248/bpb.b19-00132] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Kai Dong
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
| | - Xia Chen
- Department of Endocrinology and Metabolism, Shanghai Fourth People’s Hospital, Tongji University
| | - Liping Xie
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Lanting Yu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
| | - Mengjun Shen
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
| | - Yanping Wang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Shanshan Wu
- Shandong University Affiliated Shandong Provincial Hospital Affiliated, Department of Endocrinology and Metabolism
| | - Jiajia Wang
- Department of Endocrinology, Medical College of Soochow University
| | - Junxi Lu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Gang Wei
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
| | - Dongliang Xu
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
- Department of Urology, Changzheng Hospital, Second Military Medical University
| | - Liu Yang
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
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Fan HN, Chen W, Fan LN, Wu JT, Zhu JS, Zhang J. Macrophages-derived p38α promotes the experimental severe acute pancreatitis by regulating inflammation and autophagy. Int Immunopharmacol 2019; 77:105940. [PMID: 31655340 DOI: 10.1016/j.intimp.2019.105940] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/23/2019] [Accepted: 09/26/2019] [Indexed: 01/19/2023]
Abstract
BACKGROUND Severe acute pancreatitis (SAP) is a common threat to human health. In the present study, we aimed to investigate the underlying mechanisms by which p38α in macrophages contributes to SAP. We used conditional knockout of p38α in macrophages and p38 MAPK inhibitors to understand the effects of p38α in macrophages on caerulein-induced inflammatory responses in SAP mice models. METHODS AND MATERIALS Wild-type (WT) mice were randomly divided into three groups: a control group, SAP group, and SAP + p38MAPK inhibitor (SB203580) group, and mice with a conditional knockout (KO) of p38α in macrophages were included in a KO + SAP group. We evaluated pancreatic pathology and ultra-structure by hematoxylin and eosin staining and transmission electron microscopy. The pulmonary wet-to-dry weight ratio was calculated. The serum levels of TNF-α and IL-1β were determined by ELISA. The mRNA and protein expression of inflammatory cytokines TNF-α, IL-1β, IL-17, IL-18, MIF, and MCP-1 in pancreatic tissues were tested by qRT-PCR and immunohistochemistry analysis. The protein expression of p38, caspase-1, ULK1, LC3B and p62 in pancreatic tissues was examined by Western blotting. RESULTS The results indicated that the severity of SAP as well as the expression of the cytokines TNF-α, IL-1β, IL-17, IL-18 and MCP-1 were higher in the SAP group than those in the control group, but were lower in the SAP + SB203580 and KO + SAP groups as compared with the SAP group. The protein expression of p38, caspase-1, LC3B and p62 was increased in the SAP group than that in the control group, but this result was reversed in the SAP + SB203580 and KO + SAP groups as compared with the SAP group. In addition, the ULK1 level was significantly lower in the SAP group than that in the control group, but was increased in the SAP + SB203580 and KO + SAP groups as compared with the SAP group. CONCLUSIONS Our findings demonstrated that, macrophage derived p38α promoted the experimental severe acute pancreatitis by regulating inflammation and autophagy.
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Affiliation(s)
- Hui-Ning Fan
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Wei Chen
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Li-Na Fan
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen 361004, China
| | - Jing-Tong Wu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China
| | - Jin-Shui Zhu
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Jing Zhang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
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Zhang F, Chen C, Hu J, Su R, Zhang J, Han Z, Chen H, Li Y. Molecular mechanism of Helicobacter pylori-induced autophagy in gastric cancer. Oncol Lett 2019; 18:6221-6227. [PMID: 31788098 DOI: 10.3892/ol.2019.10976] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 07/26/2019] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori (H. pylori) is a gram-negative pathogen that colonizes gastric epithelial cells. The drug resistance rates of H. pylori have dramatically increased, causing persistent infections. Chronic infection by H. pylori is a critical cause of gastritis, peptic ulcers and even gastric cancer. In host cells, autophagy is stimulated to maintain cellular homeostasis following intracellular pathogen recognition by the innate immune defense system. However, H. pylori-induced autophagy is not consistent during acute and chronic infection. Therefore, a deeper understanding of the association between H. pylori infection and autophagy in gastric epithelial cells could aid the understanding of the mechanisms of persistent infection and the identification of autophagy-associated therapeutic targets for H. pylori infection. The present review describes the role of H. pylori and associated virulence factors in the induction of autophagy by different signaling pathways during acute infection. Additionally, the inhibition of autophagy in gastric epithelial cells during chronic infection was discussed. The present review summarized H. pylori-mediated autophagy and provided insights into its mechanism of action, suggesting the induction of autophagy as a novel therapeutic target for persistent H. pylori infection.
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Affiliation(s)
- Fan Zhang
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Cong Chen
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Jike Hu
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Ruiliang Su
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Junqiang Zhang
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Zhijian Han
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Hao Chen
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Yumin Li
- Department of Oncology Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
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Khor B, Conway KL, Omar AS, Biton M, Haber AL, Rogel N, Baxt LA, Begun J, Kuballa P, Gagnon JD, Lassen KG, Regev A, Xavier RJ. Distinct Tissue-Specific Roles for the Disease-Associated Autophagy Genes ATG16L2 and ATG16L1. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2019; 203:1820-1829. [PMID: 31451676 PMCID: PMC6761021 DOI: 10.4049/jimmunol.1800419] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 07/30/2019] [Indexed: 12/19/2022]
Abstract
The clear role of autophagy in human inflammatory diseases such as Crohn disease was first identified by genome-wide association studies and subsequently dissected in multiple mechanistic studies. ATG16L1 has been particularly well studied in knockout and hypomorph settings as well as models recapitulating the Crohn disease-associated T300A polymorphism. Interestingly, ATG16L1 has a single homolog, ATG16L2, which is independently implicated in diseases, including Crohn disease and systemic lupus erythematosus. However, the contribution of ATG16L2 to canonical autophagy pathways and other cellular functions is poorly understood. To better understand its role, we generated and analyzed the first, to our knowledge, ATG16L2 knockout mouse. Our results show that ATG16L1 and ATG16L2 contribute very distinctly to autophagy and cellular ontogeny in myeloid, lymphoid, and epithelial lineages. Dysregulation of any of these lineages could contribute to complex diseases like Crohn disease and systemic lupus erythematosus, highlighting the value of examining cell-specific effects. We also identify a novel genetic interaction between ATG16L2 and epithelial ATG16L1. These findings are discussed in the context of how these genes may contribute distinctly to human disease.
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Affiliation(s)
- Bernard Khor
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
- Pathology Service, Massachusetts General Hospital, Boston, MA 02114
| | - Kara L Conway
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Abdifatah S Omar
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Moshe Biton
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Adam L Haber
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Noga Rogel
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Leigh A Baxt
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Jakob Begun
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Petric Kuballa
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - John D Gagnon
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Kara G Lassen
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Aviv Regev
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
| | - Ramnik J Xavier
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
- Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
- The Broad Institute of Massachusetts Institute of Technology and Harvard, 7 Cambridge Center, Cambridge, MA 02142; and
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Liu J, Gao M, Nipper M, Deng J, Sharkey FE, Johnson RL, Crawford HC, Chen Y, Wang P. Activation of the intrinsic fibroinflammatory program in adult pancreatic acinar cells triggered by Hippo signaling disruption. PLoS Biol 2019; 17:e3000418. [PMID: 31513574 PMCID: PMC6742234 DOI: 10.1371/journal.pbio.3000418] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration. The mechanisms by which epithelial cells orchestrate the intrinsic fibro-inflammatory response and cell proliferation during the repair of injured tissues remains unclear. A study of molecular and cellular changes in pancreatic acinar cells suggests that the Hippo pathway acts as an intrinsic link to coordinate fibro-inflammatory response and proliferation process in epithelial cells.
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Affiliation(s)
- Jun Liu
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Ming Gao
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Michael Nipper
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Janice Deng
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Francis E Sharkey
- Department of Pathology, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Randy L Johnson
- Department of Cancer Biology, Division of Basic Science Research, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Howard C Crawford
- Department of Molecular and Integrative Physiology & Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America
| | - Yidong Chen
- Department of Epidemiology Biostatistics, UT Health San Antonio, San Antonio, Texas, United States of America
| | - Pei Wang
- Department of Cell Systems & Anatomy, UT Health San Antonio, San Antonio, Texas, United States of America
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ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis. Cell Death Dis 2019; 10:662. [PMID: 31506423 PMCID: PMC6737032 DOI: 10.1038/s41419-019-1919-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 07/31/2019] [Accepted: 08/26/2019] [Indexed: 01/20/2023]
Abstract
Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1β, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP.
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42
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Amaravadi RK, Kimmelman AC, Debnath J. Targeting Autophagy in Cancer: Recent Advances and Future Directions. Cancer Discov 2019; 9:1167-1181. [PMID: 31434711 DOI: 10.1158/2159-8290.cd-19-0292] [Citation(s) in RCA: 651] [Impact Index Per Article: 108.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 05/31/2019] [Accepted: 07/03/2019] [Indexed: 12/16/2022]
Abstract
Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specific autophagy inhibitors for cancer treatment, and review future directions for autophagy research. SIGNIFICANCE: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefit from this approach.
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Affiliation(s)
- Ravi K Amaravadi
- Abramson Cancer Center and the Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Alec C Kimmelman
- Department of Radiation Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York
| | - Jayanta Debnath
- Department of Pathology, University of California, San Francisco, California
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43
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Saloman JL, Albers KM, Cruz-Monserrate Z, Davis BM, Edderkaoui M, Eibl G, Epouhe AY, Gedeon JY, Gorelick FS, Grippo PJ, Groblewski GE, Husain SZ, Lai KK, Pandol SJ, Uc A, Wen L, Whitcomb DC. Animal Models: Challenges and Opportunities to Determine Optimal Experimental Models of Pancreatitis and Pancreatic Cancer. Pancreas 2019; 48:759-779. [PMID: 31206467 PMCID: PMC6581211 DOI: 10.1097/mpa.0000000000001335] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
At the 2018 PancreasFest meeting, experts participating in basic research met to discuss the plethora of available animal models for studying exocrine pancreatic disease. In particular, the discussion focused on the challenges currently facing the field and potential solutions. That meeting culminated in this review, which describes the advantages and limitations of both common and infrequently used models of exocrine pancreatic disease, namely, pancreatitis and exocrine pancreatic cancer. The objective is to provide a comprehensive description of the available models but also to provide investigators with guidance in the application of these models to investigate both environmental and genetic contributions to exocrine pancreatic disease. The content covers both nongenic and genetically engineered models across multiple species (large and small). Recommendations for choosing the appropriate model as well as how to conduct and present results are provided.
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Affiliation(s)
- Jami L. Saloman
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Kathryn M. Albers
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Brian M. Davis
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Mouad Edderkaoui
- Basic and Translational Pancreas Research, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA
| | - Ariel Y. Epouhe
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Jeremy Y. Gedeon
- Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA
| | - Fred S. Gorelick
- Department of Internal Medicine, Section of Digestive Diseases & Department of Cell Biology Yale University School of Medicine; Veterans Affairs Connecticut Healthcare, West Haven, CT
| | - Paul J. Grippo
- Department of Medicine, Division of Gastroenterology and Hepatology, UI Cancer Center, University of Illinois at Chicago, Chicago, IL
| | - Guy E. Groblewski
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI
| | | | - Keane K.Y. Lai
- Department of Pathology (National Medical Center), Department of Molecular Medicine (Beckman Research Institute), and Comprehensive Cancer Center, City of Hope, Duarte, CA
| | - Stephen J. Pandol
- Department of Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA
| | - Aliye Uc
- Stead Family Department of Pediatrics, University of Iowa, Stead Family Children’s Hospital, Iowa City, IA
| | - Li Wen
- Department of Pediatrics, Stanford University, Palo Alto, CA
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Oleic acid ameliorates palmitic acid-induced ER stress and inflammation markers in naive and cerulein-treated exocrine pancreas cells. Biosci Rep 2019; 39:BSR20190054. [PMID: 30992393 PMCID: PMC6522823 DOI: 10.1042/bsr20190054] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 04/06/2019] [Accepted: 04/12/2019] [Indexed: 12/13/2022] Open
Abstract
Dietary fat overload (typical to obesity) increases the risk of pancreatic pathologies through mechanisms yet to be defined. We previously showed that saturated dietary fat induces pancreatic acinar lipotoxicity and cellular stress. The endoplasmic reticulum (ER) of exocrine pancreas cells is highly developed and thus predisposed to stress. We studied the combination of saturated and unsaturated FAs in metabolic and pancreatitis like cerulein (CER)-induced stress states on cellular ER stress. Exocrine pancreas AR42J and rat primary exocrine acinar cells underwent acute (24 h) challenge with different FAs (saturated, monounsaturated) at different concentrations (250 and 500 µM) and in combination with acute CER-induced stress, and were analyzed for fat accumulation, ER stress unfolded protein response (UPR) and immune and enzyme markers. Acute exposure of AR42J and pancreatic acinar cells to different FAs and their combinations increased triglyceride accumulation. Palmitic acid significantly dose-dependently enhanced the UPR, immune factors and pancreatic lipase (PL) levels, as demonstrated by XBP1 splicing and elevation in UPR transcripts and protein levels (Xbp1,Atf6, Atf4, Chop, Tnfα, Tgfβ and Il-6). Exposure to high palmitic levels in a CER-induced stress state synergistically increased ER stress and inflammation marker levels. Exposure to oleic acid did not induce ER stress and PL levels and significantly decreased immune factors in an acute CER-induced stress state. Combination of oleic and palmitic acids significantly reduced the palmitic-induced ER stress, but did not affect the immune factor response. We show that combination of monounsaturated and saturated FAs protects from exocrine pancreatic cellular ER stress in both metabolic and CER-induced stress.
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45
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Habtezion A, Gukovskaya AS, Pandol SJ. Acute Pancreatitis: A Multifaceted Set of Organelle and Cellular Interactions. Gastroenterology 2019; 156:1941-1950. [PMID: 30660726 PMCID: PMC6613790 DOI: 10.1053/j.gastro.2018.11.082] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 10/29/2018] [Accepted: 11/15/2018] [Indexed: 12/15/2022]
Abstract
Acute pancreatitis is an inflammatory disorder of the exocrine pancreas associated with tissue injury and necrosis. The disease can be mild, involving only the pancreas, and resolve spontaneously within days or severe, with systemic inflammatory response syndrome-associated extrapancreatic organ failure and even death. Importantly, there are no therapeutic agents currently in use that can alter the course of the disease. This article emphasizes emerging findings that stressors (environmental and genetic) that cause acute pancreatitis initially cause injury to organelles of the acinar cell (endoplasmic reticulum, mitochondria, and endolysosomal-autophagy system), and that disorders in the functions of the organelles lead to inappropriate intracellular activation of trypsinogen and inflammatory pathways. We also review emerging work on the role of damage-associated molecular patterns in mediating the local and systemic inflammatory response in addition to known cytokines and chemokine pathways. In the review, we provide considerations for correction of organelle functions in acute pancreatitis to create a discussion for clinical trial treatment and design options.
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Affiliation(s)
- Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Anna S. Gukovskaya
- Division of Gastroenterology, Department of Medicine, Department of Veterans Affairs and David Geffen School of Medicine, University of California–Los Angeles, Los Angeles, California
| | - Stephen J. Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Cedars Sinai Medical Center, Los Angeles, California
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Mayerle J, Sendler M, Hegyi E, Beyer G, Lerch MM, Sahin-Tóth M. Genetics, Cell Biology, and Pathophysiology of Pancreatitis. Gastroenterology 2019; 156:1951-1968.e1. [PMID: 30660731 PMCID: PMC6903413 DOI: 10.1053/j.gastro.2018.11.081] [Citation(s) in RCA: 224] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 02/07/2023]
Abstract
Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.
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Affiliation(s)
- Julia Mayerle
- Medical Department II, University Hospital, LMU, Munich, Germany,Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Eszter Hegyi
- Institute for Translational Medicine, University of Pécs, Hungary
| | - Georg Beyer
- Medical Department II, University Hospital, LMU, Munich, Germany
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Miklós Sahin-Tóth
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118
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47
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Saluja A, Dudeja V, Dawra R, Sah RP. Early Intra-Acinar Events in Pathogenesis of Pancreatitis. Gastroenterology 2019; 156:1979-1993. [PMID: 30776339 DOI: 10.1053/j.gastro.2019.01.268] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/09/2019] [Accepted: 01/21/2019] [Indexed: 12/11/2022]
Abstract
Premature activation of digestive enzymes in the pancreas has been linked to development of pancreatitis for more than a century. Recent development of novel models to study the role of pathologic enzyme activation has led to advances in our understanding of the mechanisms of pancreatic injury. Colocalization of zymogen and lysosomal fraction occurs early after pancreatitis-causing stimulus. Cathepsin B activates trypsinogen in these colocalized organelles. Active trypsin increases permeability of these organelles resulting in leakage of cathepsin B into the cytosol leading to acinar cell death. Although trypsin-mediated cell death leads to pancreatic injury in early stages of pancreatitis, multiple parallel mechanisms, including activation of inflammatory cascades, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction in the acinar cells are now recognized to be important in driving the profound systemic inflammatory response and extensive pancreatic injury seen in acute pancreatitis. Chymotrypsin, another acinar protease, has recently been shown be play critical role in clearance of pathologically activated trypsin protecting against pancreatic injury. Mutations in trypsin and other genes thought to be associated with pathologic enzyme activation (such as serine protease inhibitor 1) have been found in familial forms of pancreatitis. Sustained intra-acinar activation of nuclear factor κB pathway seems to be key pathogenic mechanism in chronic pancreatitis. Better understanding of these mechanisms will hopefully allow us to improve treatment strategies in acute and chronic pancreatitis.
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48
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Gukovskaya AS, Gorelick FS, Groblewski GE, Mareninova OA, Lugea A, Antonucci L, Waldron RT, Habtezion A, Karin M, Pandol SJ, Gukovsky I. Recent Insights Into the Pathogenic Mechanism of Pancreatitis: Role of Acinar Cell Organelle Disorders. Pancreas 2019; 48:459-470. [PMID: 30973461 PMCID: PMC6461375 DOI: 10.1097/mpa.0000000000001298] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Acute pancreatitis (AP) is a potentially lethal inflammatory disease that lacks specific therapy. Damaged pancreatic acinar cells are believed to be the site of AP initiation. The primary function of these cells is the synthesis, storage, and export of digestive enzymes. Beginning in the endoplasmic reticulum and ending with secretion of proteins stored in zymogen granules, distinct pancreatic organelles use ATP produced by mitochondria to move and modify nascent proteins through sequential vesicular compartments. Compartment-specific accessory proteins concentrate cargo and promote vesicular budding, targeting, and fusion. The autophagy-lysosomal-endosomal pathways maintain acinar cell homeostasis by removing damaged/dysfunctional organelles and recycling cell constituents for substrate and energy. Here, we discuss studies in experimental and genetic AP models, primarily from our groups, which show that acinar cell injury is mediated by distinct mechanisms of organelle dysfunction involved in protein synthesis and trafficking, secretion, energy generation, and autophagy. These early AP events (often first manifest by abnormal cytosolic Ca signaling) in the acinar cell trigger the inflammatory and cell death responses of pancreatitis. Manifestations of acinar cell organelle disorders are also prominent in human pancreatitis. Our findings suggest that targeting specific mediators of organelle dysfunction could reduce disease severity.
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Affiliation(s)
- Anna S. Gukovskaya
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
- Department of Medicine, West Los Angeles VA Healthcare Center, Los Angeles, CA
| | - Fred S. Gorelick
- Department of Cell Biology Yale University School of Medicine, New Haven, CT
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Guy E. Groblewski
- Department of Nutritional Sciences, University of Wisconsin, Madison, WI
| | - Olga A. Mareninova
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
- Department of Medicine, West Los Angeles VA Healthcare Center, Los Angeles, CA
| | - Aurelia Lugea
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Laura Antonucci
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, La Jolla, CA
| | - Richard T. Waldron
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, La Jolla, CA
| | - Stephen J. Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Ilya Gukovsky
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles
- Department of Medicine, West Los Angeles VA Healthcare Center, Los Angeles, CA
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49
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Caberlotto L, Nguyen TP, Lauria M, Priami C, Rimondini R, Maioli S, Cedazo-Minguez A, Sita G, Morroni F, Corsi M, Carboni L. Cross-disease analysis of Alzheimer's disease and type-2 Diabetes highlights the role of autophagy in the pathophysiology of two highly comorbid diseases. Sci Rep 2019; 9:3965. [PMID: 30850634 PMCID: PMC6408545 DOI: 10.1038/s41598-019-39828-5] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 01/29/2019] [Indexed: 12/24/2022] Open
Abstract
Evidence is accumulating that the main chronic diseases of aging Alzheimer's disease (AD) and type-2 diabetes mellitus (T2DM) share common pathophysiological mechanisms. This study aimed at applying systems biology approaches to increase the knowledge of the shared molecular pathways underpinnings of AD and T2DM. We analysed transcriptomic data of post-mortem AD and T2DM human brains to obtain disease signatures of AD and T2DM and combined them with protein-protein interaction information to construct two disease-specific networks. The overlapping AD/T2DM network proteins were then used to extract the most representative Gene Ontology biological process terms. The expression of genes identified as relevant was studied in two AD models, 3xTg-AD and ApoE3/ApoE4 targeted replacement mice. The present transcriptomic data analysis revealed a principal role for autophagy in the molecular basis of both AD and T2DM. Our experimental validation in mouse AD models confirmed the role of autophagy-related genes. Among modulated genes, Cyclin-Dependent Kinase Inhibitor 1B, Autophagy Related 16-Like 2, and insulin were highlighted. In conclusion, the present investigation revealed autophagy as the central dys-regulated pathway in highly co-morbid diseases such as AD and T2DM allowing the identification of specific genes potentially involved in disease pathophysiology which could become novel targets for therapeutic intervention.
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Affiliation(s)
- Laura Caberlotto
- The Microsoft Research, University of Trento Centre for Computational Systems Biology (COSBI), Rovereto, Italy.
- Aptuit an Evotec company Drug Design and Discovery, Verona, Italy.
| | - T-Phuong Nguyen
- The Microsoft Research, University of Trento Centre for Computational Systems Biology (COSBI), Rovereto, Italy
- Life Sciences Research Unit, University of Luxembourg, Esch-sur-Alzette, Luxembourg
- Megeno S.A.6A, avenue des Hauts-FourneauxL-4362 Esch-sur-Alzette, Esch-sur-Alzette, Luxembourg
| | - Mario Lauria
- The Microsoft Research, University of Trento Centre for Computational Systems Biology (COSBI), Rovereto, Italy
- Department of Mathematics, University of Trento, Povo, Trento, Italy
| | - Corrado Priami
- The Microsoft Research, University of Trento Centre for Computational Systems Biology (COSBI), Rovereto, Italy
| | - Roberto Rimondini
- Department of Medical and Surgical Science, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Silvia Maioli
- Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
| | - Angel Cedazo-Minguez
- Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden
| | - Giulia Sita
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Fabiana Morroni
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Mauro Corsi
- Aptuit, an Evotec company, Drug Design and Discovery, Verona, Italy
| | - Lucia Carboni
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Bologna, Italy
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Merry TL, Petrov MS. The rise of genetically engineered mouse models of pancreatitis: A review of literature. Biomol Concepts 2018; 9:103-114. [DOI: 10.1515/bmc-2018-0011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 10/19/2018] [Indexed: 12/15/2022] Open
Abstract
AbstractPancreatitis is increasingly recognized as not merely a local inflammation of the pancreas but also a disease with high frequency of systemic sequelae. Current understanding of the cellular mechanisms that trigger it and affect the development of sequelae are limited. Genetically engineered mouse models can be a useful tool to study the pathophysiology of pancreatitis. This article gives an overview of the genetically engineered mouse models that spontaneously develop pancreatitis and discusses those that most closely replicate different pancreatitis hallmarks observed in humans.
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Affiliation(s)
- Troy L. Merry
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
- Discipline of Nutrition, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| | - Maxim S. Petrov
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
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