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Shimizu N, Kanemitsu S, Umemura R, Yashiro T, Kawabata R, Nishimura K, Kawasaki S, Morita K, Aoi T, Maruyama T. Mechanistic Insights into the Apoptosis of Cancer Cells Induced by a Kinase-Responsive Peptide Amphiphile. Chemistry 2025; 31:e202403658. [PMID: 39876747 DOI: 10.1002/chem.202403658] [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: 10/02/2024] [Revised: 01/27/2025] [Accepted: 01/28/2025] [Indexed: 01/30/2025]
Abstract
Organelle targeting is a useful approach in drug development for cancer therapy. Peptide amphiphiles are good candidates for targeting specific organelles because they can be engineered into a wide range of molecular structures, enabling customization for specific functional needs. We have developed a peptide amphiphile, C16-(EY)3, that can respond to tyrosine kinase activity and undergo phosphorylation inside cancer cells. C16-(EY)3 selectively induced apoptosis in cancer cells that overexpressed tyrosine kinase. The self-assembly of peptide amphiphiles on the endoplasmic reticulum (ER) membrane reduced the ER membrane fluidity and triggered ER stress. The mechanism of the cancer cell death induced by C16-(EY)3 was shown to involve phosphorylation by tyrosine kinase, ER stress induction, and the subsequent activation of caspase-4, -12, and -9, which ultimately triggered apoptosis through the activation of caspase-3 and -7. In vivo studies further validated the antitumor efficacy of C16-(EY)3, as transcutaneous administration of the peptide amphiphile inhibited tumor growth in mice. This study elucidated the mechanism of apoptosis induced by the peptide amphiphile, indicating the potential of peptide amphiphiles as organelle-targeting cancer therapeutics and providing a novel strategy for the development of selective and potent anticancer drugs.
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Affiliation(s)
- Natsumi Shimizu
- Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
| | - Sayuki Kanemitsu
- Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
| | - Riku Umemura
- Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
| | - Tomoko Yashiro
- Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
| | - Ryoko Kawabata
- Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
| | - Kanon Nishimura
- Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
| | - Shinya Kawasaki
- Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
| | - Kenta Morita
- Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
- Research Center for Membrane and Film Technology, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
| | - Takashi Aoi
- Division of Stem Cell Medicine, Graduate School of Medicine, Kobe University, 7-5-2 Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tatsuo Maruyama
- Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
- Research Center for Membrane and Film Technology, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe, 657-8501, Japan
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Cai W, Rong D, Ding J, Zhang X, Wang Y, Fang Y, Xiao J, Yang S, Wang H. Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to cancer cell apoptosis and renders synergism to overcome paclitaxel resistance in breast cancer cells. Cancer Cell Int 2024; 24:249. [PMID: 39020371 PMCID: PMC11256575 DOI: 10.1186/s12935-024-03443-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/09/2024] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND Microtubule polymerization is usually considered as the upstream of apoptotic cell death induced by taxanes, but recently published studies provide more insights into the mechanisms responsible for the antineoplastic effect of taxanes. In this study, we figure out the role of the stress-related PERK/eIF2α axis in tumor cell death upon taxane treatment along with paclitaxel resistance. METHODS Utilizing immunoblot assay, the activation status of PERK-eIF2α signaling was detected in a panel of cancer cell lines after the treatment of taxanes. The causal role of PERK-eIF2α signaling in the cancer cell apoptosis induced by taxanes was examined via pharmacological and genetic inhibitions of PERK. The relationship between microtubule polymerization and PERK-eIF2α activation was explored by immunofluorescent and immunoblotting assays. Eventaually, the combined therapeutic effect of paclitaxel (PTX) and CCT020312, a PERK agonist, was investigated in PTX-resistant breast cancer cells in vitro and in vivo. RESULTS PERK-eIF2α axis was dramatically activated by taxanes in several cancer cell types. Pharmacological or genetic inhibition of PERK efficiently impaired taxane-induced apoptotic cell death, independent of the cellular microtubule polymerization status. Moreover, PTX was able to activate the PERK/eIF2α axis in a very low concentration without triggering microtubule polymerization. In PTX-resistant breast cancer cells, the PERK/eIF2α axis was attenuated in comparison with the PTX-sensitive counterparts. Reactivation of the PERK/eIF2α axis in the PTX-resistant breast cancer cells with PERK agonist sensitized them to PTX in vitro. Combination treatment of the xenografted PTX-resistant breast tumors with PERK agonist and PTX validated the synergic effect of PTX and PERK activation in vivo. CONCLUSION Activation of the PERK/eIF2α axis is a pivotal prerequisite of taxanes to initiate cancer cell apoptosis, which is independent of the well-known microtubule polymerization-dependent manner. Simultaneous activation of PERK-eIF2α signaling would be a promising therapeutic strategy to overcome PTX resistance in breast cancer or other cancers.
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Affiliation(s)
- Wanhua Cai
- Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China
| | - Dade Rong
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China
- Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China
| | - Jiayu Ding
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China
| | - Xiaomei Zhang
- Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China
| | - Yuwei Wang
- Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China
- School of Medicine, Xizang Minzu University, No.6 Wenhui Donglu, Xianyang, 712082, China
| | - Ying Fang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China
| | - Jing Xiao
- Department of Clinical Laboratory, Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, 519000, China.
| | - Shulan Yang
- Center for Translational Medicine, the First Affiliated Hospital, Sun Yat-sen University, 58 Second Zhongshan Road, Guangzhou, 510080, China.
| | - Haihe Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Second Zhongshan Road, Guangzhou, 510080, China.
- School of Medicine, Xizang Minzu University, No.6 Wenhui Donglu, Xianyang, 712082, China.
- Clinical Medical Research Centre for Plateau Gastroenterological Disease of Xizang Autonomous Region, Xizang Minzu University, Xianyang 712082, China.
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Yu H, Yan X, Wang N, Liu X, Xue T, Li C, Zhang X. Characterization of caspase gene family in Sebastes schlegelii and their expression profiles under Aeromonas salmonicida and Vibrio anguillarum infection. Comp Biochem Physiol B Biochem Mol Biol 2024; 270:110913. [PMID: 37913865 DOI: 10.1016/j.cbpb.2023.110913] [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: 05/28/2023] [Revised: 10/27/2023] [Accepted: 10/27/2023] [Indexed: 11/03/2023]
Abstract
The caspase, functioning as a proteinase, plays a crucial role in eukaryotic cell apoptosis, regulation of apoptosis, cellular growth, differentiation, and immunity. The identification of caspase gene family in Sebastes schlegelii is of great help to understand its antimicrobial research. In S. schlegelii, we totally identified nine caspase genes, including four apoptosis initiator caspases (caspase 2, caspase 8, caspase 9 and caspase 10), four apoptosis executioners (caspase 3a, caspase 3b, caspase 6, and caspase 7) and one inflammatory executioner (caspase 1). The duplication of caspase 3 genes on chr3 and chr8 may have been facilitated by whole genome duplication (WGD) events or other complex evolutionary processes. In general, the number of caspase genes relatively conserved in high vertebrates, while exhibiting variation in teleosts. Furthermore, syntenic analysis and phylogenetic relationships analysis supported the correct classification of these caspase gene family in S. schlegelii, especially for genes with duplicated copies. Additionally, the expression patterns of these caspase genes in different tissues of S. schlegelii under healthy conditions were assessed. The results revealed that the expression levels of most caspase genes were significantly elevated in the intestine, spleen, and liver. To further investigate the potential immune functions of these caspase genes in S. schlegelii, we challenged individuals with A. salmonicida and V. anguillarum, respectively. After infection with A. salmonicida, the expression levels of caspase 1 in the liver and spleen of S. schlegelii remained consistently elevated throughout the infection time points. The expression levels of most caspase family members in the intestine exhibited significant divergence following V. anguillarum infection. This study provides a comprehensive understanding of the caspase gene families in S. schlegelii, thereby establishing a solid foundation for further investigations into the functional roles of these caspase genes.
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Affiliation(s)
- Haohui Yu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Xu Yan
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, 266071, China, Qingdao 266011, China; College of Life Sciences, Qingdao University, Qingdao 266071, China
| | - Ningning Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Xiantong Liu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Ting Xue
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China
| | - Chao Li
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China.
| | - Xiaoyan Zhang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China.
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Sahoo G, Samal D, Khandayataray P, Murthy MK. A Review on Caspases: Key Regulators of Biological Activities and Apoptosis. Mol Neurobiol 2023; 60:5805-5837. [PMID: 37349620 DOI: 10.1007/s12035-023-03433-5] [Citation(s) in RCA: 118] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 06/06/2023] [Indexed: 06/24/2023]
Abstract
Caspases are proteolytic enzymes that belong to the cysteine protease family and play a crucial role in homeostasis and programmed cell death. Caspases have been broadly classified by their known roles in apoptosis (caspase-3, caspase-6, caspase-7, caspase-8, and caspase-9 in mammals) and in inflammation (caspase-1, caspase-4, caspase-5, and caspase-12 in humans, and caspase-1, caspase-11, and caspase-12 in mice). Caspases involved in apoptosis have been subclassified by their mechanism of action as either initiator caspases (caspase-8 and caspase-9) or executioner caspases (caspase-3, caspase-6, and caspase-7). Caspases that participate in apoptosis are inhibited by proteins known as inhibitors of apoptosis (IAPs). In addition to apoptosis, caspases play a role in necroptosis, pyroptosis, and autophagy, which are non-apoptotic cell death processes. Dysregulation of caspases features prominently in many human diseases, including cancer, autoimmunity, and neurodegenerative disorders, and increasing evidence shows that altering caspase activity can confer therapeutic benefits. This review covers the different types of caspases, their functions, and their physiological and biological activities and roles in different organisms.
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Affiliation(s)
- Gayatri Sahoo
- Department of Zoology, PSSJ College, Banarpal, 759128, Odisha, India
| | - Dibyaranjan Samal
- Department of Biotechnology, Academy of Management and Information Technology (AMIT, affiliated to Utkal University), Khurda, 752057, Odisha, India
| | | | - Meesala Krishna Murthy
- Department of Allied Health Sciences, Chitkara School of Health Sciences, Chitkara University, Rajpura, Punjab, 140401, India.
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A Survey of Naturally Occurring Molecules as New Endoplasmic Reticulum Stress Activators with Selective Anticancer Activity. Cancers (Basel) 2022; 15:cancers15010293. [PMID: 36612288 PMCID: PMC9818656 DOI: 10.3390/cancers15010293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/23/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
The last century has witnessed the establishment of neoplastic disease as the second cause of death in the world. Nonetheless, the road toward desirable success rates of cancer treatments is still long and paved with uncertainty. This work aims to select natural products that act via endoplasmic reticulum (ER) stress, a known vulnerability of malignant cells, and display selective toxicity against cancer cell lines. Among an in-house chemical library, nontoxic molecules towards noncancer cells were assessed for toxicity towards cancer cells, namely the human gastric adenocarcinoma cell line AGS and the lung adenocarcinoma cell line A549. Active molecules towards at least one of these cell lines were studied in a battery of ensuing assays to clarify the involvement of ER stress and unfolded protein response (UPR) in the cytotoxic effect. Several natural products are selectively cytotoxic against malignant cells, and the effect often relies on ER stress induction. Berberine was the most promising molecule, being active against both cell models by disrupting Ca2+ homeostasis, inducing UPR target gene expression and ER-resident caspase-4 activation. Our results indicate that berberine and emodin are potential leads for the development of more potent ER stressors to be used as selective anticancer agents.
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Wang G, Fan F, Sun C, Hu Y. Looking into Endoplasmic Reticulum Stress: The Key to Drug-Resistance of Multiple Myeloma? Cancers (Basel) 2022; 14:5340. [PMID: 36358759 PMCID: PMC9654020 DOI: 10.3390/cancers14215340] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/21/2022] [Accepted: 10/27/2022] [Indexed: 09/22/2023] Open
Abstract
Multiple myeloma (MM) is the second most common hematologic malignancy, resulting from the clonal proliferation of malignant plasma cells within the bone marrow. Despite significant advances that have been made with novel drugs over the past two decades, MM patients often develop therapy resistance, especially to bortezomib, the first-in-class proteasome inhibitor that was approved for treatment of MM. As highly secretory monoclonal protein-producing cells, MM cells are characterized by uploaded endoplasmic reticulum stress (ERS), and rely heavily on the ERS response for survival. Great efforts have been made to illustrate how MM cells adapt to therapeutic stresses through modulating the ERS response. In this review, we summarize current knowledge on the mechanisms by which ERS response pathways influence MM cell fate and response to treatment. Moreover, based on promising results obtained in preclinical studies, we discuss the prospect of applying ERS modulators to overcome drug resistance in MM.
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Affiliation(s)
- Guangqi Wang
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China
| | - Fengjuan Fan
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China
| | - Chunyan Sun
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China
- Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yu Hu
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China
- Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan 430074, China
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7
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Shi W, Yao X, Fu Y, Wang Y. Interferon‑α and its effects on cancer cell apoptosis (Review). Oncol Lett 2022; 24:235. [PMID: 35720476 PMCID: PMC9185151 DOI: 10.3892/ol.2022.13355] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/19/2022] [Indexed: 11/06/2022] Open
Abstract
Interferon (IFN)-α is a cytokine that exhibits a wide range of biological activities and is used in various cancer treatments. It regulates numerous genes that serve roles in antiviral, antiproliferative and proapoptotic activities. For decades, one of the main aspects of clinical oncology has been the development of anticancer therapeutics that promote the effective elimination of cancer cells via apoptosis. However, the updated available information concerning IFN-α-induced cancer cell apoptosis needs to be assembled, so as to provide an improved theoretical reference for the basic scientific research and clinical treatment of malignant tumors. Therefore, the present review focuses on the potential effects of IFN-α in inducing cancer cell apoptosis. The biological characteristics of IFN-α, the apoptotic signaling pathways and molecular mechanisms of apoptosis caused by IFN-α are discussed in different types of cancer cells. The present review provided a comprehensive understanding of the effects of IFN-α on cancer cell apoptosis, which will aid in developing more efficient strategies to effectively control the progression of certain cancers.
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Affiliation(s)
- Weiye Shi
- College of Food Science and Biology, Hebei University of Science and Technology, Shijiazhuang, Hebei 050018, P.R. China
| | - Xu Yao
- College of Food Science and Biology, Hebei University of Science and Technology, Shijiazhuang, Hebei 050018, P.R. China
| | - Yu Fu
- College of Food Science and Biology, Hebei University of Science and Technology, Shijiazhuang, Hebei 050018, P.R. China
| | - Yingze Wang
- College of Food Science and Biology, Hebei University of Science and Technology, Shijiazhuang, Hebei 050018, P.R. China
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Kara M, Boran T, Öztaş E, Jannuzzi AT, Özden S, Özhan G. Zoledronic acid-induced oxidative damage and endoplasmic reticulum stress-mediated apoptosis in human embryonic kidney (HEK-293) cells. J Biochem Mol Toxicol 2022; 36:e23083. [PMID: 35587103 DOI: 10.1002/jbt.23083] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 02/07/2022] [Accepted: 03/01/2022] [Indexed: 11/06/2022]
Abstract
Zoledronic acid, a nitrogen-containing bisphosphonate drug, is used for the treatment of osteoporosis, Paget's disease of bone, and tumor-induced osteolysis. Zoledronic acid has also gained a place in cancer treatment due to its cytotoxic and antiproliferative effects in many cancer cells. Although zoledronic acid is considered safe, kidney damage is still one of the concerns in therapeutic doses. In the study, the aim was to assess the nephrotoxic profiles of zoledronic acid in the human embryonic kidney (HEK-293) cells. Cytotoxicity evaluation was performed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and neutral red uptake tests, while oxidative stress was performed by reactive oxygen species (ROS) production via flow cytometry, and the incomprehensible evaluation of ROS-related genes by RT-PCR and apoptosis was performed with Annexin-PI analysis in flow cytometry. The obtained result showed that zoledronic acid inhibited cell viability (IC50 values were determined as 273.16 by MTT) and cell proliferation in a concentration-dependent manner, induced ROS production, caused glutathione depletion, and increased oxidative stress index and endoplasmic reticulum (ER) stress, indicating severe cellular stress. The expression levels of oxidative damage (L-fabp, α-GST, Nrf2, and HMOX1), ER stress (CASP4, IRE1-α, GADD153, and GRP78), and apoptosis (Bcl-2, Bax, Cyt-c, p53, CASP9, CASP3, NF-κB, TNF-α, and JNK) related genes were altered as well as IRE1-α protein levels. Herein, we were the first to show that increased oxidative stress and ER stress resulting in apoptosis are the key molecular pathways in zoledronic acid-induced nephrotoxicity equivalent to clinically administered concentrations.
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Affiliation(s)
- Mehtap Kara
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Tuğçe Boran
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Ezgi Öztaş
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Ayse Tarbin Jannuzzi
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Sibel Özden
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
| | - Gül Özhan
- Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey
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The Role of Caspase-12 in Retinal Bystander Cell Death and Innate Immune Responses against MCMV Retinitis. Int J Mol Sci 2021; 22:ijms22158135. [PMID: 34360899 PMCID: PMC8348425 DOI: 10.3390/ijms22158135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/29/2021] [Accepted: 07/04/2021] [Indexed: 11/25/2022] Open
Abstract
(1) Background: caspase-12 is activated during cytomegalovirus retinitis, although its role is presently unclear. (2) Methods: caspase-12−/− (KO) or caspase-12+/+ (WT) mice were immunosup eyes were analyzed by plaque assay, TUNEL assay, immunohistochemical staining, western blotting, and real-time PCR. (3) Results: increased retinitis and a more extensive virus spread were detected in the retina of infected eyes of KO mice compared to WT mice at day 14 p.i. Compared to MCMV injected WT eyes, mRNA levels of interferons α, β and γ were significantly reduced in the neural retina of MCMV-infected KO eyes at day 14 p.i. Although similar numbers of MCMV infected cells, similar virus titers and similar numbers of TUNEL-staining cells were detected in injected eyes of both KO and WT mice at days 7 and 10 p.i., significantly lower amounts of cleaved caspase-3 and p53 protein were detected in infected eyes of KO mice at both time points. (4) Conclusions: caspase-12 contributes to caspase-3-dependent and independent retinal bystander cell death during MCMV retinitis and may also play an important role in innate immunity against virus infection of the retina.
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Rennekampff HO, Alharbi Z. Burn Injury: Mechanisms of Keratinocyte Cell Death. Med Sci (Basel) 2021; 9:medsci9030051. [PMID: 34287312 PMCID: PMC8293431 DOI: 10.3390/medsci9030051] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/27/2021] [Accepted: 07/07/2021] [Indexed: 11/16/2022] Open
Abstract
Cutaneous burn injury is associated with epidermal loss in the zone of coagulation zone and delayed tissue loss in the zone of stasis. Thus, thermal stress can trigger both necrosis and regulated cell death (RCD) or apoptosis. Experimental in vitro and in vivo work has clearly demonstrated apoptotic events of thermally injured keratinocytes that are accompanied by morphological and biochemical markers of regulated cell death. However, in vivo data for the different pathways of regulated cell death are sparse. In vitro experiments with heat-stressed human keratinocytes have demonstrated death receptor involvement (extrinsic apoptosis), calcium influx, and disruption of mitochondrial membrane potential (intrinsic apoptosis) in regulated cell death. In addition, caspase-independent pathways have been suggested in regulated cell death. Keratinocyte heat stress leads to reduced proliferation, possibly as a result of reduced keratinocyte adhesion (anoikis) or oncogene involvement. Understanding the underlying mechanisms of RCD and the skin’s responses to thermal stress may lead to improved strategies for treating cutaneous burn trauma.
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Affiliation(s)
- Hans-Oliver Rennekampff
- Department of Plastic Surgery, Hand and Burn Surgery, Burn Center, Rhein Maas Klinikum, 52146 Wuerselen, Germany
- Correspondence:
| | - Ziyad Alharbi
- Plastic Surgery and Burn Unit, Fakeeh Care & Fakeeh College of Medical Sciences, P.O. Box 2537, Jeddah 21461, Saudi Arabia;
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McGrath EP, Centonze FG, Chevet E, Avril T, Lafont E. Death sentence: The tale of a fallen endoplasmic reticulum. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:119001. [PMID: 33705817 DOI: 10.1016/j.bbamcr.2021.119001] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/12/2021] [Accepted: 02/25/2021] [Indexed: 12/17/2022]
Abstract
Endoplasmic Reticulum (ER) stress signaling is an adaptive mechanism triggered when protein folding demand overcomes the folding capacity of this compartment, thereby leading to the accumulation of improperly folded proteins. This stress signaling pathway is named the Unfolded Protein Response (UPR) and aims at restoring ER homeostasis. However, if this fails, mechanisms orienting cells towards death processes are initiated. Herein, we summarize the most recent findings connecting ER stress and the UPR with identified death mechanisms including apoptosis, necrosis, pyroptosis, ferroptosis, and autophagy. We highlight new avenues that could be investigated and controlled through actionable mechanisms in physiology and pathology.
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Affiliation(s)
| | | | - Eric Chevet
- Inserm U1242, University of Rennes, Rennes, France; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Tony Avril
- Inserm U1242, University of Rennes, Rennes, France; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
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12
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da Silva DC, Valentão P, Andrade PB, Pereira DM. Endoplasmic reticulum stress signaling in cancer and neurodegenerative disorders: Tools and strategies to understand its complexity. Pharmacol Res 2020; 155:104702. [PMID: 32068119 DOI: 10.1016/j.phrs.2020.104702] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/10/2020] [Accepted: 02/13/2020] [Indexed: 12/12/2022]
Abstract
The endoplasmic reticulum (ER) comprises a network of tubules and vesicles that constitutes the largest organelle of the eukaryotic cell. Being the location where most proteins are synthesized and folded, it is crucial for the upkeep of cellular homeostasis. Disturbed ER homeostasis triggers the activation of a conserved molecular machinery, termed the unfolded protein response (UPR), that comprises three major signaling branches, initiated by the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and the activating transcription factor 6 (ATF6). Given the impact of this intricate signaling network upon an extensive list of cellular processes, including protein turnover and autophagy, ER stress is involved in the onset and progression of multiple diseases, including cancer and neurodegenerative disorders. There is, for this reason, an increasing number of publications focused on characterizing and/or modulating ER stress, which have resulted in a wide array of techniques employed to study ER-related molecular events. This review aims to sum up the essentials on the current knowledge of the molecular biology of endoplasmic reticulum stress, while highlighting the available tools used in studies of this nature.
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Affiliation(s)
- Daniela Correia da Silva
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-213, Porto, Portugal
| | - Patrícia Valentão
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-213, Porto, Portugal
| | - Paula B Andrade
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-213, Porto, Portugal
| | - David M Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-213, Porto, Portugal.
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13
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Mariángelo JIE, Román B, Silvestri MA, Salas M, Vittone L, Said M, Mundiña‐Weilenmann C. Chemical chaperones improve the functional recovery of stunned myocardium by attenuating the endoplasmic reticulum stress. Acta Physiol (Oxf) 2020; 228:e13358. [PMID: 31385408 DOI: 10.1111/apha.13358] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 12/26/2022]
Abstract
AIM Myocardial ischaemia/reperfusion (I/R) produces structural and functional alterations depending on the duration of ischaemia. Brief ischaemia followed by reperfusion causes reversible contractile dysfunction (stunned heart) but long-lasting ischaemia followed by reperfusion can result in irreversible injury with cell death. Events during I/R can alter endoplasmic reticulum (ER) function leading to the accumulation of unfolded/misfolded proteins. The resulting ER stress induces activation of several signal transduction pathways, known as unfolded protein response (UPR). Experimental evidence shows that UPR contributes to cell death in irreversible I/R injury; however, there is still uncertainty for its occurrence in the stunned myocardium. This study investigated the ER stress response and its functional impact on the post-ischaemic cardiac performance of the stunned heart. METHODS Perfused rat hearts were subjected to 20 minutes of ischaemia followed by 30 minutes of reperfusion. UPR markers were evaluated by qRT-PCR and western blot. Post-ischaemic mechanical recovery was measured in absence and presence of two chemical chaperones: tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). RESULTS Analysis of mRNA and protein levels of various ER stress effectors demonstrated that different UPR signalling cascades, involving both pro-survival and pro-apoptotic pathways, are activated. Inhibition of the UPR with chemical chaperones improved the post-ischaemic recovery of cardiac mechanical function without affecting the I/R-induced increase in oxidative stress. CONCLUSION Our results suggest that prevention of ER stress by chemical chaperones could be a therapeutic tool to limit deterioration of the contractile function in clinical settings in which the phenomenon of myocardial stunning is present.
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Affiliation(s)
- Juan Ignacio Elio Mariángelo
- Centro de Investigaciones Cardiovasculares, CCT‐CONICET La Plata, Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Argentina
| | - Bárbara Román
- Centro de Investigaciones Cardiovasculares, CCT‐CONICET La Plata, Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Argentina
| | - María Agustina Silvestri
- Centro de Investigaciones Cardiovasculares, CCT‐CONICET La Plata, Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Argentina
| | - Margarita Salas
- Centro de Investigaciones Cardiovasculares, CCT‐CONICET La Plata, Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Argentina
| | - Leticia Vittone
- Centro de Investigaciones Cardiovasculares, CCT‐CONICET La Plata, Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Argentina
| | - Matilde Said
- Centro de Investigaciones Cardiovasculares, CCT‐CONICET La Plata, Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Argentina
| | - Cecilia Mundiña‐Weilenmann
- Centro de Investigaciones Cardiovasculares, CCT‐CONICET La Plata, Facultad de Ciencias Médicas Universidad Nacional de La Plata La Plata Argentina
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14
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Liu L, Chen M, Lin K, Xiang X, Zheng Y, Zhu S. Inhibiting Caspase-12 Mediated Inflammasome Activation protects against Oxygen-Glucose Deprivation Injury in Primary Astrocytes. Int J Med Sci 2020; 17:1936-1945. [PMID: 32788872 PMCID: PMC7415396 DOI: 10.7150/ijms.44330] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 07/02/2020] [Indexed: 12/17/2022] Open
Abstract
Stroke is one of the leading causes of death worldwide. Accumulating evidence suggests that NLRP3 inflammasome activation plays an important role in ischemic stroke injury. However, the existence of the NLRP3 inflammasome in astrocytes remains controversial. In this study, we demonstrated the presence of the NLRP3 inflammasome in primary mouse astrocytes and investigated the role of caspase-12 in NLRP3 inflammasome activation and cell injury in an in vitro astrocyte oxygen-glucose deprivation (OGD) model. Astrocytes exposed to 2, 3, and 4 h of OGD exhibited increased cell injury and apoptosis, and the protein levels of caspase-12, cleaved caspase-3, NLRP3 inflammasome components, and IL-1β were also significantly elevated. Interestingly, pretreatment with the caspase-12-specific inhibitor Z-ATAD-FMK attenuated cell injury and apoptosis and decreased the levels of NLRP3, caspase-1, IL-1β, and cleaved caspase-3 in the OGD group. In conclusion, Z-ATAD-FMK protected astrocytes against OGD-induced cell death and inhibited NLPR3-inflammasome activation. Our results indicate that caspase-12 and its potential regulation of NLRP3 inflammasome activation might be a promising target for treatment of ischemic stroke.
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Affiliation(s)
- Lu Liu
- Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People's Republic of China
| | - Manli Chen
- Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People's Republic of China
| | - Kun Lin
- Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People's Republic of China
| | - Xuwu Xiang
- Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People's Republic of China
| | - Yueying Zheng
- Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People's Republic of China
| | - Shengmei Zhu
- Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People's Republic of China
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15
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Pulmonary Endothelial Cell Apoptosis in Emphysema and Acute Lung Injury. ADVANCES IN ANATOMY EMBRYOLOGY AND CELL BIOLOGY 2019; 228:63-86. [PMID: 29288386 DOI: 10.1007/978-3-319-68483-3_4] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Apoptosis plays an essential role in homeostasis and pathogenesis of a variety of human diseases. Endothelial cells are exposed to various environmental and internal stress and endothelial apoptosis is a pathophysiological consequence of these stimuli. Pulmonary endothelial cell apoptosis initiates or contributes to progression of a number of lung diseases. This chapter will focus on the current understanding of the role of pulmonary endothelial cell apoptosis in the development of emphysema and acute lung injury (ALI) and the factors controlling pulmonary endothelial life and death.
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16
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Salvamoser R, Brinkmann K, O'Reilly LA, Whitehead L, Strasser A, Herold MJ. Characterisation of mice lacking the inflammatory caspases-1/11/12 reveals no contribution of caspase-12 to cell death and sepsis. Cell Death Differ 2019; 26:1124-1137. [PMID: 30154447 PMCID: PMC6748106 DOI: 10.1038/s41418-018-0188-2] [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] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 07/02/2018] [Accepted: 07/27/2018] [Indexed: 02/07/2023] Open
Abstract
Caspases exert critical functions in diverse cell death pathways, including apoptosis and pyroptosis, but some caspases also have roles in the processing of cytokines into their functional forms during inflammation. The roles of many caspases have been unravelled by the generation of knockout mice, but still very little is known about the overlapping functions of caspases as only a few studies report on double or triple caspase knockout mice. For example, the functions of caspase-12 in cell death and inflammation, on its own or overlapping with the functions of caspase-1 and caspase-11, are only poorly understood. Therefore, we generated a novel mutant mouse strain lacking all three inflammatory caspases, caspases-1, -11 and -12. Analysis under steady state conditions showed no obvious differences between caspase-1/11/12-/- and wildtype (WT) mice. Since caspases-1 and -11 are involved in endotoxic shock, we analysed the response of caspase-1/11/12-/- mice to high-dose LPS injection. Interestingly, we could not detect any differences in responses between caspase-1/11/12-/- mice vs. caspase-1/11 double knockout mice. Furthermore, cell lines generated from caspase-1/11/12-/- mice showed no differences in their apoptotic or necroptotic responses to a diverse set of cytotoxic drugs in vitro when compared to WT cells. Importantly, these drugs also included ER stress-inducing agents, such as thapsigargin and tunicamycin, a form of cell death for which a critical pro-apoptotic function of caspase-12 has previously been reported. Additionally, we found no differences between caspase-1/11/12-/- and WT mice in their in vivo responses to the ER stress-inducing agent, tunicamycin. Collectively, these findings reveal that caspase-12 does not have readily recognisable overlapping roles with caspases-1 and -11 in the inflammatory response induced by LPS and in necroptosis and apoptosis induced by diverse cytotoxic agents, including the ones that elicit ER stress.
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Affiliation(s)
- Ranja Salvamoser
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Kerstin Brinkmann
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Lorraine A O'Reilly
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Lachlan Whitehead
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Marco J Herold
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
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17
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Colla E. Linking the Endoplasmic Reticulum to Parkinson's Disease and Alpha-Synucleinopathy. Front Neurosci 2019; 13:560. [PMID: 31191239 PMCID: PMC6550095 DOI: 10.3389/fnins.2019.00560] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 05/15/2019] [Indexed: 11/13/2022] Open
Abstract
Accumulation of misfolded proteins is a central paradigm in neurodegeneration. Because of the key role of the endoplasmic reticulum (ER) in regulating protein homeostasis, in the last decade multiple reports implicated this organelle in the progression of Parkinson's Disease (PD) and other neurodegenerative illnesses. In PD, dopaminergic neuron loss or more broadly neurodegeneration has been improved by overexpression of genes involved in the ER stress response. In addition, toxic alpha-synuclein (αS), the main constituent of proteinaceous aggregates found in tissue samples of PD patients, has been shown to cause ER stress by altering intracellular protein traffic, synaptic vesicles transport, and Ca2+ homeostasis. In this review, we will be summarizing evidence correlating impaired ER functionality to PD pathogenesis, focusing our attention on how toxic, aggregated αS can promote ER stress and cell death.
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Affiliation(s)
- Emanuela Colla
- Bio@SNS Laboratory, Scuola Normale Superiore, Pisa, Italy
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18
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Papoff G, Presutti D, Lalli C, Bolasco G, Santini S, Manelfi C, Fustaino V, Alemà S, Ruberti G. CASP4 gene silencing in epithelial cancer cells leads to impairment of cell migration, cell-matrix adhesion and tissue invasion. Sci Rep 2018; 8:17705. [PMID: 30531914 PMCID: PMC6286322 DOI: 10.1038/s41598-018-35792-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 11/10/2018] [Indexed: 12/20/2022] Open
Abstract
Inflammatory caspases, including human caspase-4 (CASP4), play key roles in innate immune responses to promote fusion of phagosomes harboring pathogenic bacteria with lysosomes, halt intracellular replication of pathogens, maturation and secretion of pro-inflammatory cytokines. The role of inflammatory caspases in cancer cells remains poorly investigated. Here, we explored the consequences of modulating CASP4 expression levels on the migratory behavior of epithelial cancer cell lines. By a gene silencing approach and in vitro and in vivo studies we show that down-regulation of CASP4 leads to impaired cell migration and cell-matrix adhesion. This phenotype is accompanied by an increased actin cytoskeleton polymerization, changes in the overall organization of adherens junctions (AJs) and number and size of focal adhesions. Interestingly, the cell migration deficit could be reversed by epithelial growth factor treatment, and depletion of calcium ions unveiled a role of CASP4 in the novo assembly of AJs, suggesting that the role of CASP4 is not cell-autonomous. Finally, CASP4-silenced A431 cells exhibited a severe reduction in their ability to invade lung tissue, when injected into nude mice. Overall, our data support the emerging evidence that inflammatory caspases can regulate cell migration through actin remodeling and uncover a novel role of CASP4 in cancer cell behavior.
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Affiliation(s)
- Giuliana Papoff
- National Research Council, Institute of Cell Biology and Neurobiology - Campus Adriano Buzzati-Traverso Via E. Ramarini, 32 00015, Monterotondo (Rome), Italy.
| | - Dario Presutti
- National Research Council, Institute of Cell Biology and Neurobiology - Campus Adriano Buzzati-Traverso Via E. Ramarini, 32 00015, Monterotondo (Rome), Italy
| | - Cristiana Lalli
- National Research Council, Institute of Cell Biology and Neurobiology - Campus Adriano Buzzati-Traverso Via E. Ramarini, 32 00015, Monterotondo (Rome), Italy
| | - Giulia Bolasco
- Epigenetics and Neurobiology Unit, European Molecular Biology Laboratory (EMBL), Rome, Via E. Ramarini 32 Monterotondo (Rome), Italy
| | - Simonetta Santini
- National Research Council, Institute of Cell Biology and Neurobiology - Campus Adriano Buzzati-Traverso Via E. Ramarini, 32 00015, Monterotondo (Rome), Italy
| | - Candida Manelfi
- National Research Council, Institute of Cell Biology and Neurobiology - Campus Adriano Buzzati-Traverso Via E. Ramarini, 32 00015, Monterotondo (Rome), Italy
| | - Valentina Fustaino
- National Research Council, Institute of Cell Biology and Neurobiology - Campus Adriano Buzzati-Traverso Via E. Ramarini, 32 00015, Monterotondo (Rome), Italy
| | - Stefano Alemà
- National Research Council, Institute of Cell Biology and Neurobiology - Campus Adriano Buzzati-Traverso Via E. Ramarini, 32 00015, Monterotondo (Rome), Italy
| | - Giovina Ruberti
- National Research Council, Institute of Cell Biology and Neurobiology - Campus Adriano Buzzati-Traverso Via E. Ramarini, 32 00015, Monterotondo (Rome), Italy.
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19
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Neuritin Attenuates Neuronal Apoptosis Mediated by Endoplasmic Reticulum Stress In Vitro. Neurochem Res 2018; 43:1383-1391. [PMID: 29790068 PMCID: PMC6006204 DOI: 10.1007/s11064-018-2553-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 03/28/2018] [Accepted: 05/16/2018] [Indexed: 12/11/2022]
Abstract
Neuritin is an extracellular glycophosphatidylinositol-linked protein that promotes neuronal survival, differentiation, function, and repair, but the exact mechanism of this neuroprotective effect remains unclear. Meanwhile, endoplasmic reticulum stress (ERS) induced apoptosis is attracting increased attention. In this work, we hypothesized that neuritin inhibited ERS to protect cortical neurons. To check this hypothesis, we exposed primary cultured cortical neurons to oxygen and glucose deprivation (OGD) for 45 min followed by reperfusion (R) to activate ERS. We then performed resuscitation for 6, 12, 24, and 48 h. ERS-related factors such as glucose-regulated protein 78 (GRP78), caspase-12 and CHOP were detected by Western blotting and quantitative real-time polymerase chain reaction assay. Apoptosis was assessed by Annexin V binding and propidium iodide staining. Ultrastructural changes of endoplasmic reticulum were observed under a transmission electron microscope. Results showed that GRP78 expression significantly increased at 12, 24, and 48 h and peaked at 24 h. Caspase-12 and CHOP expression significantly increased in a time-dependent manner at 12, 24, and 48 h. GRP78, caspase-12 and CHOP expression as well as apoptosis rate of primary cultured neurons and the ultrastructural changes of endoplasmic reticulum in the OGD/R + neuritin group significantly improved compared with the OGD/R group. In conclusion, the neuroprotection function of neuritin may be involved in ERS pathways.
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20
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Mycobacterium fortuitum-induced ER-Mitochondrial calcium dynamics promotes calpain/caspase-12/caspase-9 mediated apoptosis in fish macrophages. Cell Death Discov 2018. [PMID: 29531827 PMCID: PMC5841318 DOI: 10.1038/s41420-018-0034-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mycobacterium fortuitum is a natural fish pathogen. It induces apoptosis in headkidney macrophages (HKM) of catfish, Clarias sp though the mechanism remains largely unknown. We observed M. fortuitum triggers calcium (Ca2+) insult in the sub-cellular compartments which elicits pro-apototic ER-stress factor CHOP. Alleviating ER-stress inhibited CHOP and attenuated HKM apoptosis implicating ER-stress in the pathogenesis of M. fortuitum. ER-stress promoted calpain activation and silencing the protease inhibited caspase-12 activation. The study documents the primal role of calpain/caspase-12 axis on caspase-9 activation in M. fortuitum-pathogenesis. Mobilization of Ca2+ from ER to mitochondria led to increased mitochondrial Ca2+ (Ca2+)m load,, mitochondrial permeability transition (MPT) pore opening, altered mitochondrial membrane potential (ΔΨm) and cytochrome c release eventually activating the caspase-9/-3 cascade. Ultra-structural studies revealed close apposition of ER and mitochondria and pre-treatment with (Ca2+)m-uniporter (MUP) blocker ruthenium red, reduced Ca2+ overload suggesting (Ca2+)m fluxes are MUP-driven and the ER-mitochondria tethering orchestrates the process. This is the first report implicating role of sub-cellular Ca2+ in the pathogenesis of M. fortuitum. We summarize, the dynamics of Ca2+ in sub-cellular compartments incites ER-stress and mitochondrial dysfunction, leading to activation of pro-apoptotic calpain/caspase-12/caspase-9 axis in M. fortuitum-infected HKM.
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21
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Songane M, Khair M, Saleh M. An updated view on the functions of caspases in inflammation and immunity. Semin Cell Dev Biol 2018; 82:137-149. [PMID: 29366812 DOI: 10.1016/j.semcdb.2018.01.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Revised: 12/21/2017] [Accepted: 01/02/2018] [Indexed: 12/14/2022]
Abstract
The binary classification of mammalian caspases as either apoptotic or inflammatory is now obsolete. Emerging data indicate that all mammalian caspases are intricately involved in the regulation of inflammation and immunity. They participate in embryonic and adult tissue homeostasis, control leukocyte differentiation, activation and effector functions, and mediate innate and adaptive immunity signaling. Caspases also promote host resistance by regulating anti-oxidant defense and pathogen clearance through regulation of phagosomal maturation, actin dynamics and phagosome-lysosome fusion. Beyond apoptosis, they regulate inflammatory cell death, eliciting rapid pyroptosis of infected cells, while inhibiting necroptosis-mediated tissue destruction and chronic inflammation. In this review, we describe the cellular and molecular mechanisms underlying non-apoptotic functions of caspases in inflammation and immunity and provide an updated view of their functions as central regulators of tissue homeostasis and host defense.
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Affiliation(s)
- Mario Songane
- Department of Medicine, McGill University, Montréal, Québec H3G 0B1, Canada
| | - Mostafa Khair
- Department of Medicine, McGill University, Montréal, Québec H3G 0B1, Canada
| | - Maya Saleh
- Department of Medicine, McGill University, Montréal, Québec H3G 0B1, Canada.
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22
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Kang SJ, Lee YJ, Kang SG, Cho S, Yoon W, Lim JH, Min SH, Lee TH, Kim BM. Caspase-4 is essential for saikosaponin a-induced apoptosis acting upstream of caspase-2 and γ-H2AX in colon cancer cells. Oncotarget 2017; 8:100433-100448. [PMID: 29245990 PMCID: PMC5725032 DOI: 10.18632/oncotarget.22247] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 09/30/2017] [Indexed: 11/25/2022] Open
Abstract
Saikosaponin a (SSa), a bioactive phytochemical from Bupleurum, triggers sequential caspase-2 and caspase-8 activation, and thereby induces caspase-mediated apoptosis in human colon carcinoma (HCC) cells. However, the upstream mechanism of caspase-2 activation remains unknown. Therefore, we investigated the signaling mechanisms underlying SSa-induced caspase activation and apoptosis in HCC cells. SSa treatment triggered marked antitumor effects, especially in HCC cells, in a cell culture model and a mouse xenograft model. SSa also induced the activation of several endoplasmic reticulum (ER) stress signals. Specifically, caspase-4, a critical regulator of ER stress-induced apoptosis, was activated significantly after SSa treatment. Mechanistically, selective inhibition of caspase-4 suppressed SSa-induced apoptosis, colony inhibition, and the activation of caspase-3, -8, and -2, but not vice versa. Consistent with the important role of caspase-2 in the DNA damage response, SSa induced DNA damage, as evidenced by a cytokinesis-block micronucleus assay, single-cell gel electrophoresis, and an increase in the levels of γ-H2AX, a DNA damage marker. Moreover, inhibition of caspase-4 activation inhibited SSa-induced histone H2AX phosphorylation. Taken together, these results suggest that caspase-4 is an upstream regulator of SSa-induced DNA damage and caspase activation in HCC cells. Given that SSa-induced apoptosis appeared to be specific to certain cell types including HCC cells, SSa may be a promising cancer therapy agent in certain types of cancer.
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Affiliation(s)
- Su Jin Kang
- The Medical Research Center for Globalization of Herbal Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-Do 38610, Republic of Korea.,Department of Preventive Medicine, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-Do 38610, Republic of Korea
| | - Young Joon Lee
- The Medical Research Center for Globalization of Herbal Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-Do 38610, Republic of Korea.,Department of Preventive Medicine, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-Do 38610, Republic of Korea
| | - Sung Gu Kang
- Department of Urology, Korea University College of Medicine, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Soyoung Cho
- Department of Science for Aging, Yonsei University, Seodaemun-gu, Seoul 03722, Republic of Korea.,Severance Integrative Research Institute for Cerebral & Cardiovascular Diseases (SIRIC), Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Wonsuck Yoon
- Allergy Immunology Center, Korea University College of Medicine, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Ji Hong Lim
- Department of Biomedical Chemistry, Konkuk University, Chungju, Chungbuk 27478, Republic of Korea
| | - Sang-Hyun Min
- New Drug Development Center, DGMIF, Dong-gu, Daegu 41061, Republic of Korea
| | - Tae Ho Lee
- Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Byeong Mo Kim
- Severance Integrative Research Institute for Cerebral & Cardiovascular Diseases (SIRIC), Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Republic of Korea
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23
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Affiliation(s)
- Jason A Glab
- Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Victoria 3086, Australia
| | - Marcel Doerflinger
- Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Victoria 3086, Australia
| | - Hamsa Puthalakath
- Department of Biochemistry & Genetics, La Trobe Institute for Molecular Science, La Trobe University, Kingsbury Drive, Bundoora, Victoria 3086, Australia
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24
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Khan MM, Yang WL, Brenner M, Bolognese AC, Wang P. Cold-inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress. Sci Rep 2017; 7:41363. [PMID: 28128330 PMCID: PMC5269663 DOI: 10.1038/srep41363] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 12/19/2016] [Indexed: 12/12/2022] Open
Abstract
Cold-inducible RNA-binding protein (CIRP), released into the circulation during sepsis, causes lung injury via an as yet unknown mechanism. Since endoplasmic reticulum (ER) stress is associated with acute lung injury (ALI), we hypothesized that CIRP causes ALI via induction of ER stress. To test this hypothesis, we studied the lungs of wild-type (WT) and CIRP knockout (KO) mice at 20 h after induction of sepsis by cecal ligation and puncture (CLP). WT mice had significantly more severe ALI than CIRP KO mice. Lung ER stress markers (BiP, pIRE1α, sXBP1, CHOP, cleaved caspase-12) were increased in septic WT mice, but not in septic CIRP KO mice. Effector pathways downstream from ER stress – apoptosis, NF-κB (p65), proinflammatory cytokines (IL-6, IL-1β), neutrophil chemoattractants (MIP-2, KC), neutrophil infiltration (MPO activity), lipid peroxidation (4-HNE), and nitric oxide (iNOS) – were significantly increased in WT mice, but only mildly elevated in CIRP KO mice. ER stress markers were increased in the lungs of healthy WT mice treated with recombinant murine CIRP, but not in the lungs of TLR4 KO mice. This suggests CIRP directly induces ER stress via TLR4 activation. In summary, CIRP induces lung ER stress and downstream responses to cause sepsis-associated ALI.
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Affiliation(s)
- Mohammad Moshahid Khan
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Weng-Lang Yang
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.,Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY 11030, USA.,Elmezzi Graduate School of Molecular Medicine, Manhasset, NY 11030, USA
| | - Max Brenner
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
| | - Alexandra Cerutti Bolognese
- Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY 11030, USA.,Elmezzi Graduate School of Molecular Medicine, Manhasset, NY 11030, USA
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.,Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY 11030, USA.,Elmezzi Graduate School of Molecular Medicine, Manhasset, NY 11030, USA
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Interferon α Induces the Apoptosis of Cervical Cancer HeLa Cells by Activating both the Intrinsic Mitochondrial Pathway and Endoplasmic Reticulum Stress-Induced Pathway. Int J Mol Sci 2016; 17:ijms17111832. [PMID: 27827850 PMCID: PMC5133833 DOI: 10.3390/ijms17111832] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 10/14/2016] [Accepted: 10/27/2016] [Indexed: 02/02/2023] Open
Abstract
The interferon α (IFN-α) has been often used as a sensitizing agent for the treatment of various malignancies such as hepatocellular carcinoma, malignant melanoma, and renal cell cancer by promoting the apoptosis of thesetumor cell types. However, the effect of IFN-α on cervical cancer remains unknown. In this study, HeLa cells were used as a testing model for the treatment of IFN-α on cervical cancer. The results indicate that IFN-α markedly inhibits the proliferation and induces the apoptosis of HeLa cells. The activation of caspase 3, the up-regulation of both Bim and cleaved poly (ADP-ribose) polymerase (PARP) 1, the down-regulation of Bcl-xL, as well as the release of cytochrome c from mitochondria were significantly induced upon IFN-α treatment, indicating that the intrinsic apoptotic pathway could be activated by IFN-α treatment. In addition, caspase 4—which is involved in the endoplasmic reticulum (ER) stress-induced apoptosis—was activated in response to IFN-α treatment. Knocking down caspase 4 by small interfering RNA (siRNA) markedly reduced the IFN-α-mediated cell apoptosis. However, no significant changes in the expressions of caspases 8 and 10 were observed upon IFN-α treatment, indicating that the apoptosis caused by IFN-α might be independent of the extrinsic apoptotic pathway. These findings suggest that IFN-α may possess anti-cervical cancer capacity by activating cell apoptosis via the intrinsic mitochondrial pathway and caspase-4-related ER stress-induced pathway.
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Jang Y, Kim J, Ko JW, Kwon YH. Homocysteine induces PUMA-mediated mitochondrial apoptosis in SH-SY5Y cells. Amino Acids 2016; 48:2559-2569. [PMID: 27339788 DOI: 10.1007/s00726-016-2280-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 06/14/2016] [Indexed: 11/24/2022]
Abstract
Previous studies have reported that homocysteine induced endoplasmic reticulum (ER) stress in neuronal cells, proposing the underlying mechanism by which it could induce neurotoxicity. Induction of pro-apoptotic transcription factor C/EBP homologous protein (CHOP) and activation of caspase-4 by calpain have been suggested to be an important route in inducing apoptosis in response to ER stress. In this study, we investigated the molecular pathway of homocysteine-induced apoptosis in caspase-4 deficient SH-SY5Y human neuroblastoma cells. Homocysteine significantly increased mRNA levels of CHOP and p53, resulting in the upregulation of their downstream target gene, p53 up-regulated modulator of apoptosis (PUMA). In cells treated with homocysteine, Bcl-2-associated X protein (BAX) protein levels, cytochrome c release from the mitochondria, and caspase-9 activation were significantly increased. Consistently, a caspase-9 inhibitor significantly alleviated homocysteine-induced cytotoxicity. Significantly lower BAX mRNA levels and caspase-9 activation were observed in cells transfected with siRNA for PUMA. Taken together, our findings suggest that PUMA would be involved in the possible crosstalk between the ER and the mitochondria in the homocysteine-induced apoptosis of caspase-4 deficient SH-SY5Y cells.
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Affiliation(s)
- Yumi Jang
- Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea
| | - Juhae Kim
- Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea
| | - Je Won Ko
- Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea
| | - Young Hye Kwon
- Department of Food and Nutrition, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea. .,Research Institute of Human Ecology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826, Korea.
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García de la Cadena S, Massieu L. Caspases and their role in inflammation and ischemic neuronal death. Focus on caspase-12. Apoptosis 2016; 21:763-77. [DOI: 10.1007/s10495-016-1247-0] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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28
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Anania VG, Yu K, Gnad F, Pferdehirt RR, Li H, Ma TP, Jeon D, Fortelny N, Forrest W, Ashkenazi A, Overall CM, Lill JR. Uncovering a Dual Regulatory Role for Caspases During Endoplasmic Reticulum Stress-induced Cell Death. Mol Cell Proteomics 2016; 15:2293-307. [PMID: 27125827 PMCID: PMC4937505 DOI: 10.1074/mcp.m115.055376] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Indexed: 12/13/2022] Open
Abstract
Many diseases are associated with endoplasmic reticulum (ER) stress, which results from an accumulation of misfolded proteins. This triggers an adaptive response called the "unfolded protein response" (UPR), and prolonged exposure to ER stress leads to cell death. Caspases are reported to play a critical role in ER stress-induced cell death but the underlying mechanisms by which they exert their effect continue to remain elusive. To understand the role caspases play during ER stress, a systems level approach integrating analysis of the transcriptome, proteome, and proteolytic substrate profile was employed. This quantitative analysis revealed transcriptional profiles for most human genes, provided information on protein abundance for 4476 proteins, and identified 445 caspase substrates. Based on these data sets many caspase substrates were shown to be downregulated at the protein level during ER stress suggesting caspase activity inhibits their cellular function. Additionally, RNA sequencing revealed a role for caspases in regulation of ER stress-induced transcriptional pathways and gene set enrichment analysis showed expression of multiple gene targets of essential transcription factors to be upregulated during ER stress upon inhibition of caspases. Furthermore, these transcription factors were degraded in a caspase-dependent manner during ER stress. These results indicate that caspases play a dual role in regulating the cellular response to ER stress through both post-translational and transcriptional regulatory mechanisms. Moreover, this study provides unique insight into progression of the unfolded protein response into cell death, which may help identify therapeutic strategies to treat ER stress-related diseases.
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Affiliation(s)
| | - Kebing Yu
- From the Departments of ‡Protein Chemistry
| | | | | | | | | | - Diana Jeon
- From the Departments of ‡Protein Chemistry
| | - Nikolaus Fortelny
- ‖Departments of Oral Biological and Medical Sciences, and University of British Columbia, Vancouver, British Columbia, Canada
| | | | | | - Christopher M Overall
- ‖Departments of Oral Biological and Medical Sciences, and University of British Columbia, Vancouver, British Columbia, Canada
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Iurlaro R, Muñoz-Pinedo C. Cell death induced by endoplasmic reticulum stress. FEBS J 2015; 283:2640-52. [PMID: 26587781 DOI: 10.1111/febs.13598] [Citation(s) in RCA: 785] [Impact Index Per Article: 78.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 10/27/2015] [Accepted: 11/11/2015] [Indexed: 02/07/2023]
Abstract
The endoplasmic reticulum is an organelle with multiple functions. The synthesis of transmembrane proteins and proteins that are to be secreted occurs in this organelle. Many conditions that impose stress on cells, including hypoxia, starvation, infections and changes in secretory needs, challenge the folding capacity of the cell and promote endoplasmic reticulum stress. The cellular response involves the activation of sensors that transduce signaling cascades with the aim of restoring homeostasis. This is known as the unfolded protein response, which also intersects with the integrated stress response that reduces protein synthesis through inactivation of the initiation factor eIF2α. Central to the unfolded protein response are the sensors PERK, IRE1 and ATF6, as well as other signaling nodes such as c-Jun N-terminal kinase 1 (JNK) and the downstream transcription factors XBP1, ATF4 and CHOP. These proteins aim to restore homeostasis, but they can also induce cell death, which has been shown to occur by necroptosis and, more commonly, through the regulation of Bcl-2 family proteins (Bim, Noxa and Puma) that leads to mitochondrial apoptosis. In addition, endoplasmic reticulum stress and proteotoxic stress have been shown to induce TRAIL receptors and activation of caspase-8. Endoplasmic reticulum stress is a common feature in the pathology of numerous diseases because it plays a role in neurodegeneration, stroke, cancer, metabolic diseases and inflammation. Understanding how cells react to endoplasmic reticulum stress can accelerate discovery of drugs against these diseases.
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Affiliation(s)
- Raffaella Iurlaro
- Cell Death Regulation Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain
| | - Cristina Muñoz-Pinedo
- Cell Death Regulation Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Spain
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30
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Rashid HO, Yadav RK, Kim HR, Chae HJ. ER stress: Autophagy induction, inhibition and selection. Autophagy 2015; 11:1956-1977. [PMID: 26389781 DOI: 10.1080/15548627.2015.1091141] [Citation(s) in RCA: 609] [Impact Index Per Article: 60.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
An accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) leads to stress conditions. To mitigate such circumstances, stressed cells activate a homeostatic intracellular signaling network cumulatively called the unfolded protein response (UPR), which orchestrates the recuperation of ER function. Macroautophagy (hereafter autophagy), an intracellular lysosome-mediated bulk degradation pathway for recycling and eliminating wornout proteins, protein aggregates, and damaged organelles, has also emerged as an essential protective mechanism during ER stress. These 2 systems are dynamically interconnected, and recent investigations have revealed that ER stress can either stimulate or inhibit autophagy. However, the stress-associated molecular cues that control the changeover switch between induction and inhibition of autophagy are largely obscure. This review summarizes the crosstalk between ER stress and autophagy and their signaling networks mainly in mammalian-based systems. Additionally, we highlight current knowledge on selective autophagy and its connection to ER stress.
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Affiliation(s)
- Harun-Or Rashid
- a Department of Pharmacology ; Medical School; Chonbuk National University
| | - Raj Kumar Yadav
- a Department of Pharmacology ; Medical School; Chonbuk National University
| | - Hyung-Ryong Kim
- b Department of Dental Pharmacology ; College of Dentistry; Wonkwang University
| | - Han-Jung Chae
- a Department of Pharmacology ; Medical School; Chonbuk National University
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Fernández A, Ordóñez R, Reiter RJ, González-Gallego J, Mauriz JL. Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis. J Pineal Res 2015. [PMID: 26201382 DOI: 10.1111/jpi.12264] [Citation(s) in RCA: 392] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Endoplasmic reticulum (ER) is a dynamic organelle that participates in a number of cellular functions by controlling lipid metabolism, calcium stores, and proteostasis. Under stressful situations, the ER environment is compromised, and protein maturation is impaired; this causes misfolded proteins to accumulate and a characteristic stress response named unfolded protein response (UPR). UPR protects cells from stress and contributes to cellular homeostasis re-establishment; however, during prolonged ER stress, UPR activation promotes cell death. ER stressors can modulate autophagy which in turn, depending of the situation, induces cell survival or death. Interactions of different autophagy- and apoptosis-related proteins and also common signaling pathways have been found, suggesting an interplay between these cellular processes, although their dynamic features are still unknown. A number of pathologies including metabolic, neurodegenerative and cardiovascular diseases, cancer, inflammation, and viral infections are associated with ER stress, leading to a growing interest in targeting components of the UPR as a therapeutic strategy. Melatonin has a variety of antioxidant, anti-inflammatory, and antitumor effects. As such, it modulates apoptosis and autophagy in cancer cells, neurodegeneration and the development of liver diseases as well as other pathologies. Here, we review the effects of melatonin on the main ER stress mechanisms, focusing on its ability to regulate the autophagic and apoptotic processes. As the number of studies that have analyzed ER stress modulation by this indole remains limited, further research is necessary for a better understanding of the crosstalk between ER stress, autophagy, and apoptosis and to clearly delineate the mechanisms by which melatonin modulates these responses.
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Affiliation(s)
- Anna Fernández
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Raquel Ordóñez
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
| | - José L Mauriz
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
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Simard JC, Vallieres F, de Liz R, Lavastre V, Girard D. Silver nanoparticles induce degradation of the endoplasmic reticulum stress sensor activating transcription factor-6 leading to activation of the NLRP-3 inflammasome. J Biol Chem 2015; 290:5926-39. [PMID: 25593314 DOI: 10.1074/jbc.m114.610899] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
In the past decade, the increasing amount of nanoparticles (NP) and nanomaterials used in multiple applications led the scientific community to investigate the potential toxicity of NP. Many studies highlighted the cytotoxic effects of various NP, including titanium dioxide, zinc oxide, and silver nanoparticles (AgNP). In a few studies, endoplasmic reticulum (ER) stress was found to be associated with NP cytotoxicity leading to apoptosis in different cell types. In this study, we report for the first time that silver nanoparticles of 15 nm (AgNP15), depending on the concentration, induced different signature ER stress markers in human THP-1 monocytes leading to a rapid ER stress response with degradation of the ATF-6 sensor. Also, AgNP15 induced pyroptosis and activation of the NLRP-3 inflammasome as demonstrated by the processing and increased activity of caspase-1 and secretion of IL-1β and ASC (apoptosis-associated speck-like protein containing a CARD domain) pyroptosome formation. Transfection of THP-1 cells with siRNA targeting NLRP-3 decreased the AgNP15-induced IL-1β production. The absence of caspase-4 expression resulted in a significant reduction of pro-IL-1β. However, caspase-1 activity was significantly higher in caspase-4-deficient cells when compared with WT cells. Inhibition of AgNP15-induced ATF-6 degradation with Site-2 protease inhibitors completely blocked the effect of AgNP15 on pyroptosis and secretion of IL-1β, indicating that ATF-6 is crucial for the induction of this type of cell death. We conclude that AgNP15 induce degradation of the ER stress sensor ATF-6, leading to activation of the NLRP-3 inflammasome regulated by caspase-4 in human monocytes.
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Affiliation(s)
- Jean-Christophe Simard
- From the Laboratoire de recherche en inflammation et physiologie des granulocytes, Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Québec H7V1B7, Canada
| | - Francis Vallieres
- From the Laboratoire de recherche en inflammation et physiologie des granulocytes, Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Québec H7V1B7, Canada
| | - Rafael de Liz
- From the Laboratoire de recherche en inflammation et physiologie des granulocytes, Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Québec H7V1B7, Canada
| | - Valerie Lavastre
- From the Laboratoire de recherche en inflammation et physiologie des granulocytes, Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Québec H7V1B7, Canada
| | - Denis Girard
- From the Laboratoire de recherche en inflammation et physiologie des granulocytes, Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Québec H7V1B7, Canada
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Sun C, Wang H, Chen S, Li Z, Li S, Wang J. Recombinant Clostridium difficile toxin B induces endoplasmic reticulum stress in mouse colonal carcinoma cells. Acta Biochim Biophys Sin (Shanghai) 2014; 46:973-81. [PMID: 25274332 DOI: 10.1093/abbs/gmu091] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Clostridium difficile is the main cause of antibiotic-associated diarrhea and pseudomembranous colitis in humans and animals. Its pathogenicity is primarily linked to the secretion of two exotoxins (TcdA and TcdB). Although great progress in the toxic mechanism of TcdA and TcdB has been achieved, there are many conflicting reports about the apoptotic mechanism. More importantly, apoptotic endoplasmic reticulum (ER) stress has been reported in cells treated with Shiga toxins-another kind of cytotoxins that can cause diarrhea and colitis. Herein we checked whether TcdB can induce ER stress. The results showed that recombinant TcdB (rTcdB) activated molecular markers of unfolded protein response, suggesting that rTcdB induced ER stress in CT26 cells. However, rTcdB did not induce the up-regulation of C/EBP homologous protein (CHOP), a classic mediator of apoptotic ER stress, but it activated the precursor of cysteine aspartic acid-specific protease 12 (caspase-12), a controversial mediator of apoptotic ER stress. Besides, glucosyltransferase activity-deficient mutant recombinant TcdB induced ER stress, though it has no cytotoxic or cytopathic effect on CT26 cells. Altogether, these data demonstrated that ER stress induced by rTcdB is glucosyltransferase-independent, indicating that ER stress induced by rTcdB is non-apoptotic. This work also offers us a new insight into the molecular mechanism of CHOP protein expression regulation and the role of CHOP expression in ER stress.
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Affiliation(s)
- Chunli Sun
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Haiying Wang
- School of Light Industry and Food Sciences, South China University of Technology, Guangzhou 510006, China
| | - Shuyi Chen
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Zhendong Li
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
| | - Shan Li
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China School of Light Industry and Food Sciences, South China University of Technology, Guangzhou 510006, China
| | - Jufang Wang
- School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China
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Abstract
Beyond their contribution to basic metabolism, the major cellular organelles, in particular mitochondria, can determine whether cells respond to stress in an adaptive or suicidal manner. Thus, mitochondria can continuously adapt their shape to changing bioenergetic demands as they are subjected to quality control by autophagy, or they can undergo a lethal permeabilization process that initiates apoptosis. Along similar lines, multiple proteins involved in metabolic circuitries, including oxidative phosphorylation and transport of metabolites across membranes, may participate in the regulated or catastrophic dismantling of organelles. Many factors that were initially characterized as cell death regulators are now known to physically or functionally interact with metabolic enzymes. Thus, several metabolic cues regulate the propensity of cells to activate self-destructive programs, in part by acting on nutrient sensors. This suggests the existence of "metabolic checkpoints" that dictate cell fate in response to metabolic fluctuations. Here, we discuss recent insights into the intersection between metabolism and cell death regulation that have major implications for the comprehension and manipulation of unwarranted cell loss.
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Affiliation(s)
- Douglas R Green
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
| | - Lorenzo Galluzzi
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, F-75006 Paris, France. Université Paris Descartes/Paris V; Sorbonne Paris Cité; F-75005 Paris, France. INSERM, U1138, F-94805 Villejuif, France
| | - Guido Kroemer
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, F-75006 Paris, France. Université Paris Descartes/Paris V; Sorbonne Paris Cité; F-75005 Paris, France. INSERM, U1138, F-94805 Villejuif, France. Metabolomics and Cell Biology Platforms, Gustave Roussy, F-94805 Villejuif, France. Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, F-75015 Paris, France.
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Zhang Y, Liu W, Zhou Y, Ma C, Li S, Cong B. Endoplasmic reticulum stress is involved in restraint stress-induced hippocampal apoptosis and cognitive impairments in rats. Physiol Behav 2014; 131:41-8. [DOI: 10.1016/j.physbeh.2014.04.014] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2013] [Revised: 02/25/2014] [Accepted: 04/04/2014] [Indexed: 01/05/2023]
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36
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Endoplasmic reticulum stress in cerebral ischemia. Neurochem Int 2014; 68:18-27. [DOI: 10.1016/j.neuint.2014.02.001] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 12/27/2013] [Accepted: 02/03/2014] [Indexed: 12/20/2022]
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Born EJ, Hartman SV, Holstein SA. Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells. Blood Cancer J 2013; 3:e167. [PMID: 24317089 PMCID: PMC3877421 DOI: 10.1038/bcj.2013.64] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2013] [Accepted: 11/06/2013] [Indexed: 12/30/2022] Open
Abstract
Multiple myeloma is characterized by the production of substantial quantities of monoclonal protein. We have previously demonstrated that select inhibitors of the isoprenoid biosynthetic pathway (IBP) induce apoptosis of myeloma cells via inhibition of Rab geranylgeranylation, leading to disruption of monoclonal protein trafficking and induction of the unfolded protein response (UPR) pathway. Heat-shock protein 90 (HSP90) inhibitors disrupt protein folding and are currently under clinical investigation in myeloma. The effects of combining IBP and HSP90 inhibitors on cell death, monoclonal protein trafficking, the UPR and chaperone regulation were investigated in monoclonal protein-producing cells. An enhanced induction of cell death was observed following treatment with IBP and HSP90 inhibitors, which occurred through both ER stress and non-ER stress pathways. The HSP90 inhibitor 17-AAG abrogated the effects of the IBP inhibitors on intracellular monoclonal protein levels and localization as well as induction of the UPR in myeloma cells. Disparate effects on chaperone expression were observed in myeloma vs amyloid light chain cells. Here we demonstrate that the novel strategy of targeting MP trafficking in concert with HSP90 enhances myeloma cell death via a complex modulation of ER stress, UPR, and cell death pathways.
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Affiliation(s)
- E J Born
- Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
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Cao A, Li Q, Yin P, Dong Y, Shi H, Wang L, Ji G, Xie J, Wu D. Curcumin induces apoptosis in human gastric carcinoma AGS cells and colon carcinoma HT-29 cells through mitochondrial dysfunction and endoplasmic reticulum stress. Apoptosis 2013; 18:1391-1402. [PMID: 23881281 DOI: 10.1007/s10495-013-0871-1] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In the present study, we investigate the effect of curcumin, a major active component isolated from rhizomes of Curcuma longa, on the cytotoxicity of three human carcinoma cell lines (AGS, HT-29 and MGC803) in gastrointestinal tract and a normal gastric epithelial cell line GES-1, and the mechanism of curcumin-induced apoptosis. The results indicated that curcumin inhibited the gastrointestinal carcinoma cell growth in a dose-dependent manner and cytotoxicity was more towards the gastric carcinoma cell AGS and colon carcinoma cell HT-29 compared to normal gastric cell GES-1, and increased externalization of phosphatidylserine residue was observed by Annexin V/PI staining in the two cell lines. Treatment of AGS and HT-29 cells with curcumin enhanced the cleavage of procaspase-3, -7, -8 and -9. Meanwhile, curcumin induced endoplasmic reticulum (ER) stress and mitochondrial dysfunction as evidenced by up-regulation of CCAAT/enhancer binding protein homologous protein (CHOP), phosphorylation of JNK and down-regulation of SERCA2ATPase, release of cytochrome c, decrease of Bcl-2 and reduction of mitochondrial membrane potential in both AGS and HT-29 cells. Overexpression of bax, total JNK, phospho-FADD and total FADD were also observed in curcumin-treated HT-29 cells. Moreover, curcumin decreased cytosolic and ER Ca(2+), but increased mitochondrial Ca(2+) in the two cell lines. 2-Aminoethoxydiphenyl borate, an antagonist of inositol 1, 4, 5-triphosphate receptor, partly blocked curcumin-induced cytosolic Ca(2+) decrease in AGS and HT-29 cells. Additionally, carbonyl cyanide m-chlorophenylhydrazone, an inhibitor of mitochondrial Ca(2+) uptake, reversed curcumin-triggered AGS and HT-29 cells growth inhibition. siRNA to CHOP markedly reduced curcumin-induced apoptosis. These results suggest that curcumin can impact on ER stress and mitochondria functional pathways in AGS and HT-29 cells, death receptor pathway was also involved in curcumin-treated HT-29 cells, thus identifying specific well-defined molecular mechanisms that may be targeted by therapeutic strategies.
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Affiliation(s)
- Aili Cao
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qi Li
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Peihao Yin
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Yang Dong
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hailian Shi
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Li Wang
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Guang Ji
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Jianqun Xie
- Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
| | - Dazheng Wu
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
- Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
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A novel RING finger E3 ligase RNF186 regulate ER stress-mediated apoptosis through interaction with BNip1. Cell Signal 2013; 25:2320-33. [PMID: 23896122 DOI: 10.1016/j.cellsig.2013.07.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 07/04/2013] [Accepted: 07/22/2013] [Indexed: 01/08/2023]
Abstract
Disturbances in the normal functions of the endoplasmic reticulum (ER) can lead to the accumulation of unfolded proteins and disturbance of Ca(2+) regulation within the lumen of ER, and arouse a series of complicated response termed unfolded protein response (UPR), which is aimed initially at reestablishing homeostasis and normal physiology but can ultimately trigger cell death if the UPR fails to compensate for damage. Here we show that ER locating human RING finger E3 ligase RNF186 participates in the process of ER stress-mediated apoptosis. Overexpression of RNF186 stimulates upregulation of ER sensor proteins and rapid transmission of ER Ca(2+) in Hela cells, while RNF186 knockdown exhibits a moderate degree of resistance to ER stress, indicating RNF186 can arouse stress signaling at ER. We further identified the Bcl-2 family protein BNip1 as one of the substrates of RNF186. BNip1 co-localizes with RNF186 at ER and is poly-ubiquitinated by RNF186 through K29 and K63 linkage in vivo. This modification promotes BNip1 transportation to mitochondria but has no influence on its protein level. The half-life of RNF186 is prolonged under ER stress, probably because of the inhibition on its self-ubiquitination and subsequent degradation by proteasomes. In addition, the ubiquitination of BNip1 is greatly enhanced when ER stress occurred, possibly due to RNF186 accumulation. More importantly, knockdown of BNip1 attenuates the stress signals at ER induced by RNF186. These results collectively indicate that BNip1 functions as a downstream modulator of RNF186 to direct ER stress-associated apoptotic signaling. Our study might reveal a novel E3 ligase-mediated mechanism for modulating ER stress.
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Hirata Y, Sugie A, Matsuda A, Matsuda S, Koyasu S. TAK1-JNK axis mediates survival signal through Mcl1 stabilization in activated T cells. THE JOURNAL OF IMMUNOLOGY 2013; 190:4621-6. [PMID: 23547112 DOI: 10.4049/jimmunol.1202809] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
TAK1, a member of MAPK kinase kinase (MAPKK-K) family, can activate JNK, p38 MAPK, and NF-κB signaling pathways. Although targeted gene disruption studies have demonstrated that TAK1 plays a critical role in T cell functions, precise functions of downstream mediators remain elusive. We used the chemical compound LL-Z1640-2, which preferentially suppressed MAPK activation but not NF-κB signal downstream of TAK1. LL-Z1640-2 blocked TCR-induced T cell proliferation and activation, confirming that a TAK1-mediated MAPK signal is essential for T cell activation. LL-Z1640-2 induced apoptosis of activated mouse splenic T cells in a caspase- and caspase-activated DNase-dependent manner. TAK1-JNK pathway, which is activated downstream of IL-2R, induced the phosphorylation of antiapoptotic protein Mcl1 in activated T cells, resulting in the stabilization of Mcl1 protein. Our data uncover that among signal transduction pathways downstream of TAK1, JNK mediates a survival program through Mcl1 stabilization downstream of IL-2R in activated T cells and that blockade of TAK1-JNK pathway can eliminate activated T cells by apoptosis.
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Affiliation(s)
- Yasuko Hirata
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan
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Venero JL, Burguillos MA, Joseph B. Caspases playing in the field of neuroinflammation: old and new players. Dev Neurosci 2013; 35:88-101. [PMID: 23445938 DOI: 10.1159/000346155] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 10/15/2012] [Indexed: 11/19/2022] Open
Abstract
Neuroinflammation is a complex immune response against the harmful effects of diverse stimuli within the central nervous system. Caspases are a family of intracellular cysteine proteases that mediate proteolytic events indispensable for transduction of signaling pathway-controlling biological phenomena such as apoptosis and inflammation. To date, 14 players have been identified in mammals. For many years, caspases were simply divided into 'apoptotic' and 'proinflammatory' caspases and this classification remains useful to some extent. However, increasing evidence indicates that many of these so-called apoptotic caspases also exert nonapoptotic functions. In addition, the role of certain members of the supposed inflammatory caspases in the inflammatory process per se has also been discussed. In this review, we highlight the role for 'apoptotic' and 'proinflammatory' caspases in the regulation of the inflammation response with a special focus on the central nervous system.
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Affiliation(s)
- Jose L Venero
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain
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Loss of endoplasmic reticulum Ca2+ homeostasis: contribution to neuronal cell death during cerebral ischemia. Acta Pharmacol Sin 2013; 34:49-59. [PMID: 23103622 DOI: 10.1038/aps.2012.139] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The loss of Ca(2+) homeostasis during cerebral ischemia is a hallmark of impending neuronal demise. Accordingly, considerable cellular resources are expended in maintaining low resting cytosolic levels of Ca(2+). These include contributions by a host of proteins involved in the sequestration and transport of Ca(2+), many of which are expressed within intracellular organelles, including lysosomes, mitochondria as well as the endoplasmic reticulum (ER). Ca(2+) sequestration by the ER contributes to cytosolic Ca(2+) dynamics and homeostasis. Furthermore, within the ER Ca(2+) plays a central role in regulating a host of physiological processes. Conversely, impaired ER Ca(2+) homeostasis is an important trigger of pathological processes. Here we review a growing body of evidence suggesting that ER dysfunction is an important factor contributing to neuronal injury and loss post-ischemia. Specifically, the contribution of the ER to cytosolic Ca(2+) elevations during ischemia will be considered, as will the signalling cascades recruited as a consequence of disrupting ER homeostasis and function.
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LIU CHINYU, YANG JAISING, HUANG SHIHMING, CHIANG JOHUA, CHEN MINGHUA, HUANG LIJIAU, HA HOYU, FUSHIYA SHINJI, KUO SHENGCHU. Smh-3 induces G2/M arrest and apoptosis through calcium-mediated endoplasmic reticulum stress and mitochondrial signaling in human hepatocellular carcinoma Hep3B cells. Oncol Rep 2012; 29:751-62. [DOI: 10.3892/or.2012.2166] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 11/02/2012] [Indexed: 11/06/2022] Open
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Tanjore H, Lawson WE, Blackwell TS. Endoplasmic reticulum stress as a pro-fibrotic stimulus. Biochim Biophys Acta Mol Basis Dis 2012. [PMID: 23201247 DOI: 10.1016/j.bbadis.2012.11.011] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Current evidence suggests a prominent role for endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in fibrotic conditions affecting a number of internal organs, including the lungs, liver, GI tract, kidney, and heart. ER stress enhances the susceptibility of structural cells, in most cases the epithelium, to pro-fibrotic stimuli. Studies suggest that ER stress facilitates fibrotic remodeling through activation of pro-apoptotic pathways, induction of epithelial-mesenchymal transition, and promotion of inflammatory responses. While genetic mutations that lead to ER stress underlie some cases of fibrosis, including lung fibrosis secondary to mutations in surfactant protein C (SFTPC), a variety of other factors can cause ER stress. These ER stress inducing factors include metabolic abnormalities, oxidative stress, viruses, and environmental exposures. Interestingly, the ability of the ER to maintain homeostasis under stress diminishes with age, potentially contributing to the fact that fibrotic disorders increase in incidence with aging. Taken together, underlying ER stress and UPR pathways are emerging as important determinants of fibrotic remodeling in different forms of tissue fibrosis. Further work is needed to better define the mechanisms by which ER stress facilitates progressive tissue fibrosis. In addition, it remains to be seen whether targeting ER stress and the UPR could have therapeutic benefit. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
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Affiliation(s)
- Harikrishna Tanjore
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
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Costa RO, Lacor PN, Ferreira IL, Resende R, Auberson YP, Klein WL, Oliveira CR, Rego AC, Pereira CMF. Endoplasmic reticulum stress occurs downstream of GluN2B subunit of N-methyl-d-aspartate receptor in mature hippocampal cultures treated with amyloid-β oligomers. Aging Cell 2012; 11:823-33. [PMID: 22708890 DOI: 10.1111/j.1474-9726.2012.00848.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting both the hippocampus and the cerebral cortex. Reduced synaptic density that occurs early in the disease process seems to be partially due to the overactivation of N-methyl-d-aspartate receptors (NMDARs) leading to excitotoxicity. Recently, we demonstrated that amyloid-beta oligomers (AβO), the species implicated in synaptic loss during the initial disease stages, induce endoplasmic reticulum (ER) stress in cultured neurons. Here, we investigated whether AβO trigger ER stress by an NMDAR-dependent mechanism leading to neuronal dysfunction and analyzed the contribution of GluN2A and GluN2B subunits of this glutamate receptor. Our data revealed that AβO induce ER stress in mature hippocampal cultures, activating ER stress-associated sensors and increasing the levels of the ER chaperone GRP78. We also showed that AβO induce NADPH oxidase (NOX)-mediated superoxide production downstream of GluN2B and impairs ER and cytosolic Ca2+ homeostasis. These events precede changes in cell viability and activation of the ER stress-mediated apoptotic pathway, which was associated with translocation of the transcription factor GADD153 / CHOP to the nucleus and occurred by a caspase-12-independent mechanism. Significantly, ER stress took place after AβO interaction with GluN2B subunits. In addition, AβO-induced ER stress and hippocampal dysfunction were prevented by ifenprodil, an antagonist of GluN2B subunits, while the GluN2A antagonist NVP-AAM077 only slightly attenuated AβO-induced neurotoxicity. Taken together, our results highlight the role of GluN2B subunit of NMDARs on ER stress-mediated hippocampal dysfunction caused by AβO suggesting that it might be a potential therapeutic target during the early stages of AD.
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Affiliation(s)
- Rui O Costa
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
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46
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Endoplasmic reticulum stress contributes to arsenic trioxide-induced apoptosis in drug-sensitive and -resistant leukemia cells. Leuk Res 2012; 36:1526-35. [PMID: 22959511 DOI: 10.1016/j.leukres.2012.08.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 07/13/2012] [Accepted: 08/11/2012] [Indexed: 11/22/2022]
Abstract
This study characterized the role of endoplasmic reticulum stress (ERS)-related pathways in arsenic trioxide-induced apoptosis in multidrug-resistant leukemia K562/ADM cells. Arsenic trioxide exposure led to much significant induction of apoptosis in K562/ADM cells than the parental K562 cells, and the chaperone proteins glucose-regulated protein 78, CHOP/GADD153, X-box binding protein-1 and caspase-12 were activated to varying degrees. Furthermore, arsenic trioxide stimulation led to inhibition of P-glycoprotein and Bcl-2 expression. This study demonstrates a missing link between arsenic trioxide and ERS-induced apoptosis, and suggests that the greater effects obtained in drug-resistant K562/ADM cells may be mediated by downregulation of P-glycoprotein and Bcl-2 expression.
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47
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Dou G, Sreekumar PG, Spee C, He S, Ryan SJ, Kannan R, Hinton DR. Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction. Free Radic Biol Med 2012; 53:1111-22. [PMID: 22781655 PMCID: PMC3454510 DOI: 10.1016/j.freeradbiomed.2012.06.042] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Revised: 06/12/2012] [Accepted: 06/28/2012] [Indexed: 01/29/2023]
Abstract
Endoplasmic reticulum (ER) stress is linked to several pathological conditions including age-related macular degeneration. Excessive ER stress initiates cell death cascades which are mediated, in part, through mitochondrial dysfunction. Here, we identify αB crystallin as an important regulator of ER stress-induced cell death. Retinal pigment epithelial (RPE) cells from αB crystallin (-/-) mice, and human RPE cells transfected with αB crystallin siRNA, are more vulnerable to ER stress induced by tunicamycin. ER stress-mediated cell death is associated with increased levels of reactive oxygen species, depletion of glutathione in mitochondria, decreased superoxide dismutase activity, increased release of cytochrome c, and activation of caspases 3 and 4. The ER stress signaling inhibitors, salubrinal and 4-(2-aminoethyl) benzenesulfonyl fluoride, decrease mitochondrial damage and reduce RPE apoptosis induced by ER stress. Prolonged ER stress decreases levels of αB crystallin, thus exacerbating mitochondrial dysfunction. Overexpression of αB crystallin protects RPE cells from ER stress-induced apoptosis by attenuating increases in Bax, CHOP, mitochondrial permeability transition, and cleaved caspase 3. Thus, these data collectively demonstrate that αB crystallin provides critical protection of mitochondrial function during ER stress-induced RPE apoptosis.
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Affiliation(s)
- Guorui Dou
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Parameswaran G Sreekumar
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
| | - Christine Spee
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Shikun He
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Stephen J Ryan
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - Ram Kannan
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
| | - David R Hinton
- Arnold and Beckman Macular Research Center, Doheny Eye Institute, 1355 San Pablo St, Los Angeles, CA 90033, USA
- Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA
- Corresponding Author: David R Hinton MD, Department of Pathology, 2011 Zonal Avenue, HMR 209, Los Angeles, CA 90033, USA. Tel.: + 1 323 442 6617; Fax: + 1 323 442 6688.
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Zhu Y, Zhu Y, Yin H, Zhou H, Wan X, Zhu J, Zhang T. All-trans-retinoic acid induces short forelimb malformation during mouse embryo development by inhibiting chondrocyte maturation rather than by evoking excess cell death. Toxicol Lett 2012; 211:172-86. [DOI: 10.1016/j.toxlet.2012.03.801] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Revised: 03/22/2012] [Accepted: 03/25/2012] [Indexed: 02/07/2023]
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Lim MJ, Ahn JY, Han Y, Yu CH, Kim MH, Lee SLO, Lim DS, Song JY. Acriflavine enhances radiosensitivity of colon cancer cells through endoplasmic reticulum stress-mediated apoptosis. Int J Biochem Cell Biol 2012; 44:1214-22. [PMID: 22564437 DOI: 10.1016/j.biocel.2012.04.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Revised: 04/27/2012] [Accepted: 04/30/2012] [Indexed: 10/28/2022]
Abstract
Radiotherapy (RT) is one of the most effective tools in the clinical treatment of cancer. Because the tumor suppressor p53 plays a central role in radiation-mediated responses, including cell cycle-arrest and apoptosis, a number of studies have suggested that p53 could be a useful therapeutic target of anti-cancer agents. Accordingly, we sought to discover a new agent capable of increasing p53 activity. HCT116 colon cancer cells, containing wild-type p53, were stably transfected with a p53 responsive-luciferase (p53-Luc) reporter gene. A cell-based high-throughput screen of 7920 synthetic small molecules was performed in duplicate. Of the screened compounds, acriflavine (ACF) significantly increased p53-Luc activity in a concentration-dependent manner without causing toxicity. Pretreatment with ACF enhanced the induction of p53 protein expression and phosphorylation on serine 15 by γ-irradiation. Clonogenic assays showed that ACF pretreatment also potentiated radiation-induced cell death. The combination of irradiation and ACF treatment induced mitochondrial release of cytochrome c and significant activation of caspase-3 with PARP cleavage in colon cancer cells, demonstrating typical apoptotic cell death. Combined treatment with ACF and radiation increased the expression of Bax and Bad, while decreasing expression of Bcl-2. In addition, the ACF/radiation treatment combination induced endoplasmic reticulum (ER) stress responses mediated by IRE1α (inositol-requiring transmembrane kinase and endonuclease 1α), eIF-2α (eukaryotic initiation factor 2α), caspase-2/12, and CHOP (C/EBP homologous protein). The knockdown of IRE1α by siRNA inhibited the apoptotic cell death induced by ACF/radiation treatment. In vivo studies showed that combined treatment with ACF and radiation significantly inhibited the growth of tumors in colorectal cancer xenografted mice. These results indicate that ACF acts through p53-dependent mitochondrial pathways and ER stress signals, and could be a promising radiosensitizer.
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Affiliation(s)
- Min-Jin Lim
- Department of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea
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50
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Sun J, Yu Y, Deubel V. Japanese encephalitis virus NS1' protein depends on pseudoknot secondary structure and is cleaved by caspase during virus infection and cell apoptosis. Microbes Infect 2012; 14:930-40. [PMID: 22504173 DOI: 10.1016/j.micinf.2012.03.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 03/15/2012] [Accepted: 03/19/2012] [Indexed: 02/06/2023]
Abstract
Japanese encephalitis virus (JEV) is a flavivirus with a complex life cycle involving mosquito vectors that mainly target birds and pigs, and causes severe encephalitis in children in Asia. Neurotropic flaviviruses of the JEV serogroup have a particular characteristic of expressing a unique nonstructural NS1' protein, which is a prolongation of NS1 at the C terminus by 52 amino acids derived from a pseudoknot-driven-1 translation frameshift. Protein NS1' is associated with virus neuro-invasiveness. In this study, the need of the pseudoknot structure for NS1' synthesis was confirmed. By using a specific antibody against the prolonged peptide, NS1' was found to be absent from the JEV SA14-14-2 vaccine strain, resulting from a single nucleotide silent mutation in the pseudoknot. A partial cleavage of NS1' at a specific site of its C-terminal appendix recognized by caspases and inhibited by caspase inhibitors suggests a unique feature of intracellular NS1'.
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Affiliation(s)
- Jin Sun
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China
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