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Chang CP, Wu CW, Chern Y. Metabolic dysregulation in Huntington's disease: Neuronal and glial perspectives. Neurobiol Dis 2024; 201:106672. [PMID: 39306013 DOI: 10.1016/j.nbd.2024.106672] [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: 08/18/2024] [Revised: 09/15/2024] [Accepted: 09/16/2024] [Indexed: 09/29/2024] Open
Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutant huntingtin protein with an abnormal CAG/polyQ expansion in the N-terminus of HTT exon 1. HD is characterized by progressive neurodegeneration and metabolic abnormalities, particularly in the brain, which accounts for approximately 20 % of the body's resting metabolic rate. Dysregulation of energy homeostasis in HD includes impaired glucose transporters, abnormal functions of glycolytic enzymes, changes in tricarboxylic acid (TCA) cycle activity and enzyme expression in the basal ganglia and cortical regions of both HD mouse models and HD patients. However, current understanding of brain cell behavior during energy dysregulation and its impact on neuron-glia crosstalk in HD remains limited. This review provides a comprehensive summary of the current understanding of the differences in glucose metabolism between neurons and glial cells in HD and how these differences contribute to disease development compared with normal conditions. We also discuss the potential impact of metabolic shifts on neuron-glia communication in HD. A deeper understanding of these metabolic alterations may reveal potential therapeutic targets for future drug development.
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Affiliation(s)
- Ching-Pang Chang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ching-Wen Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
| | - Yijuang Chern
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
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Umeki Y, Hala D, Petersen LH. Optimization of an in situ liver perfusion method to evaluate hepatic function of juvenile American alligators (Alligator mississippiensis). Biol Open 2024; 13:bio060532. [PMID: 39189399 PMCID: PMC11381930 DOI: 10.1242/bio.060532] [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: 05/08/2024] [Accepted: 06/28/2024] [Indexed: 08/28/2024] Open
Abstract
American alligators (Alligator mississippiensis) are a sentinel species whose health is representative of environmental quality. However, their susceptibility to various natural or anthropogenic stressors is yet to be comprehensively studied. Understanding hepatic function in such assessments is essential as the liver is the central organ in the metabolic physiology of an organism, and therefore influences its adaptive capability. In this study, a novel liver perfusion system was developed to study the hepatic physiology of juvenile alligators. First, a cannulation procedure was developed for an in situ liver perfusion preparation. Second, an optimal flow rate of 0.5 ml/min/g liver was determined based on the oxygen content in the effluent perfusate. Third, the efficacy of the liver preparation was tested by perfusing the liver with normoxic or hypoxic Tyrode's buffer while various biomarkers of hepatic function were monitored in the effluent perfusate. Our results showed that in the normoxic perfusion, the aspartate transferase (AST) and lactate/pyruvate ratio in the perfusate remained stable and within an acceptable physiological range for 6 h. In contrast, hypoxia exposure significantly increased the lactate/pyruvate ratio in the perfusate after 2 h, indicating an induction of anaerobic metabolism. These results suggest that the perfused liver remained viable during the perfusion period and exhibited the expected physiological response under hypoxia exposure. The liver perfusion system developed in this study provides an experimental framework with which to study the basic hepatic physiology of alligators and elucidate the effects of environmental or anthropogenic stressors on the metabolic physiology of this sentinel species.
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Affiliation(s)
- Yu Umeki
- Department of Marine Biology, Texas A&M University at Galveston, 200 Seawolf Parkway, Galveston, TX, 77553,USA
| | - David Hala
- Department of Marine Biology, Texas A&M University at Galveston, 200 Seawolf Parkway, Galveston, TX, 77553,USA
| | - Lene Hebsgaard Petersen
- Department of Marine Biology, Texas A&M University at Galveston, 200 Seawolf Parkway, Galveston, TX, 77553,USA
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Song DH, Jo JY, Kim CH, Kim MH, Cho IA, Shin JK, Choi WJ, Baek JC. Hypoxia-Regulated Proteins: Expression in Endometrial Cancer and Their Association with Clinicopathologic Features. Diagnostics (Basel) 2024; 14:1735. [PMID: 39202223 PMCID: PMC11353210 DOI: 10.3390/diagnostics14161735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/08/2024] [Accepted: 08/08/2024] [Indexed: 09/03/2024] Open
Abstract
BACKGROUND Hypoxia-regulated proteins (HIF-1α and GLUT-1) have been identified as prognostic markers in various cancers; however, their role in endometrial cancer remains unclear. This study aimed to evaluate HIF-1α and GLUT-1 expression in endometrial cancer and correlate their expression with clinicopathological features. MATERIALS AND METHODS A tissue microarray (TMA) was constructed using specimens from a retrospective cohort of 51 endometrial cancer patients who underwent hysterectomy at the Gyeongsang National University Hospital between 2002 and 2009. Clinicopathologic data were collected from electronic medical records, and HIF-1α and GLUT-1 expressions were assessed in the tumor tissue. RESULTS GLUT-1 expression in endometrial cancer was categorized as mosaic, central, or diffuse. Most patients (56.0%) exhibited a central pattern, followed by diffuse (32.0%) and mosaic (12.0%) patterns. GLUT-1 expression was not significantly associated with histologic grade (p = 0.365). HIF-1α expression in immune cells, but not tumor cells, was significantly associated with a higher histologic grade. A higher proportion of HIF-1α-positive immune cells, using both thresholds (≤1% vs. >1% and ≤5% vs. >5%), was significantly associated with higher histologic grade (p = 0.032 and p = 0.048, respectively). In addition, a higher proportion of HIF-1α-positive immune cells was significantly associated with a diffuse GLUT-1 expression pattern using >5% as a threshold. There were no significant differences in the proportion of HIF-1α-positive immune cells between groups stratified by age, tumor size, or invasion depth, regardless of whether the 1% or 5% threshold for HIF-1α positivity was used. CONCLUSIONS A higher proportion of HIF-1α-positive immune cells is associated with endometrial cancers with higher histologic grade and diffuse GLUT1 expression patterns. These findings suggest a potential role for HIF-1α as a prognostic marker and highlight the need for further studies into the role of HIF-1α in the tumor microenvironment.
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Affiliation(s)
- Dae Hyun Song
- Department of Pathology, Gyeongsang National University School of Medicine, Gyeongsang National University Changwon Hospital, 11, Changwon-si 51472, Republic of Korea;
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.J.); (C.H.K.); (M.H.K.); (I.A.C.); (J.K.S.); (W.J.C.)
| | - Jae Yoon Jo
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.J.); (C.H.K.); (M.H.K.); (I.A.C.); (J.K.S.); (W.J.C.)
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - Cho Hee Kim
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.J.); (C.H.K.); (M.H.K.); (I.A.C.); (J.K.S.); (W.J.C.)
| | - Min Hye Kim
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.J.); (C.H.K.); (M.H.K.); (I.A.C.); (J.K.S.); (W.J.C.)
- Department of Pathology, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - In Ae Cho
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.J.); (C.H.K.); (M.H.K.); (I.A.C.); (J.K.S.); (W.J.C.)
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - Jeong Kyu Shin
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.J.); (C.H.K.); (M.H.K.); (I.A.C.); (J.K.S.); (W.J.C.)
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - Won Jun Choi
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.J.); (C.H.K.); (M.H.K.); (I.A.C.); (J.K.S.); (W.J.C.)
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju 52727, Republic of Korea
| | - Jong Chul Baek
- Institute of Medical Science, Gyeongsang National University, Jinju 52727, Republic of Korea; (J.Y.J.); (C.H.K.); (M.H.K.); (I.A.C.); (J.K.S.); (W.J.C.)
- Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Gyeongsang National University Changwon Hospital, 11, Changwon-si 51472, Republic of Korea
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Abyar S, Huang L, Husiev Y, Bretin L, Chau B, Ramu V, Wildeman JH, Belfor K, Wijaya LS, van der Noord VE, Harms AC, Siegler MA, Le Dévédec SE, Bonnet S. Oxygen-Dependent Interactions between the Ruthenium Cage and the Photoreleased Inhibitor in NAMPT-Targeted Photoactivated Chemotherapy. J Med Chem 2024; 67:11086-11102. [PMID: 38924492 PMCID: PMC11247496 DOI: 10.1021/acs.jmedchem.4c00589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 06/28/2024]
Abstract
Photoactivated chemotherapy agents form a new branch of physically targeted anticancer agents with potentially lower systemic side effects for patients. On the other hand, limited information exists on the intracellular interactions between the photoreleased metal cage and the photoreleased anticancer inhibitor. In this work, we report a new biological study of the known photoactivated compound Ru-STF31 in the glioblastoma cancer cell line, U87MG. Ru-STF31 targets nicotinamide phosphoribosyltransferase (NAMPT), an enzyme overexpressed in U87MG. Ru-STF31 is activated by red light irradiation and releases two photoproducts: the ruthenium cage and the cytotoxic inhibitor STF31. This study shows that Ru-STF31 can significantly decrease intracellular NAD+ levels in both normoxic (21% O2) and hypoxic (1% O2) U87MG cells. Strikingly, NAD+ depletion by light activation of Ru-STF31 in hypoxic U87MG cells could not be rescued by the addition of extracellular NAD+. Our data suggest an oxygen-dependent active role of the ruthenium photocage released by light activation.
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Affiliation(s)
- Selda Abyar
- Leiden
Institute of Chemistry, Leiden University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
- Leiden
Academic Centre for Drug Research, Leiden
University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Luojiao Huang
- Leiden
Academic Centre for Drug Research, Leiden
University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Yurii Husiev
- Leiden
Institute of Chemistry, Leiden University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Ludovic Bretin
- Leiden
Institute of Chemistry, Leiden University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Bobby Chau
- Leiden
Institute of Chemistry, Leiden University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
- Leiden
Academic Centre for Drug Research, Leiden
University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Vadde Ramu
- Leiden
Institute of Chemistry, Leiden University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Jacob Hendricus Wildeman
- Leiden
Academic Centre for Drug Research, Leiden
University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Kimberley Belfor
- Leiden
Academic Centre for Drug Research, Leiden
University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Lukas S. Wijaya
- Leiden
Academic Centre for Drug Research, Leiden
University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Vera E. van der Noord
- Leiden
Academic Centre for Drug Research, Leiden
University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Amy C. Harms
- Leiden
Academic Centre for Drug Research, Leiden
University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Maxime A. Siegler
- Department
of Chemistry, Johns Hopkins University, 3400 N Charles St, Baltimore, Maryland 21218, United States
| | - Sylvia E. Le Dévédec
- Leiden
Academic Centre for Drug Research, Leiden
University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
| | - Sylvestre Bonnet
- Leiden
Institute of Chemistry, Leiden University, Gorlaeus Laboratories, PO Box 9502, Leiden 2300 RA, The Netherlands
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Yang X, Feng H, Kim J, Ti G, Wang L, Wang K, Song D. PRR34-AS1 promotes mitochondrial division and glycolytic reprogramming in hepatocellular carcinoma cells through upregulation of MIEF2. Acta Biochim Biophys Sin (Shanghai) 2024; 56:1604-1617. [PMID: 38779765 PMCID: PMC11659787 DOI: 10.3724/abbs.2024083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 03/20/2024] [Indexed: 05/25/2024] Open
Abstract
LncRNA PRR34-AS1 overexpression promotes the proliferation and invasion of hepatocellular carcinoma (HCC) cells, but whether it affects HCC energy metabolism remains unclear. Mitochondrial division and glycolytic reprogramming play important roles in tumor development. In this study, the differential expression of PRR34-AS1 is explored via TCGA analysis, and higher levels of PRR34-AS1 are detected in patients with liver cancer than in healthy individuals. A series of experiments, such as CCK-8, PCR, and immunofluorescence staining, reveal that the proliferation, invasion, glycolysis, and mitochondrial division of PRR34-AS1-overexpressing hepatoma cells are significantly promoted. TCGA analysis and immunohistochemistry reveal high expression of the mitochondrial dynamin MIEF2 in liver cancer tissues. Dual-luciferase reporter assays confirm that miR-498 targets and binds to mitochondrial elongation factor 2 (MIEF2). In addition, we show that PRR34-AS1 can sponge miR-498. Therefore, we further investigate the effects of the lncRNA PRR34-AS1/miR-498/MIEF2 axis on the growth, glucose metabolism, and mitochondrial division in hepatocellular carcinoma cells. A series of experiments are performed on hepatocellular carcinoma cells after different treatments. The results show that the proliferative activity, invasive ability, and glycolytic level of hepatocellular carcinoma cells are decreased in HCC cells with low PRR34-AS1 expression, and the miR-498 expression level is increased in these cells. Inhibition of miR-498 or overexpression of MIEF2 restored the proliferative activity, invasive ability, glycolysis, and mitochondrial division in hepatocellular carcinoma cells. Thus, PRR34-AS1 regulates MIEF2 by sponging miR-498, thereby promoting mitochondrial division, mediating glycolytic reprogramming and ultimately driving the growth and invasion of HCC cells. Furthermore, in vivo mouse experiments yield results similar to those of the in vitro experiments, verifying the above results.
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Affiliation(s)
- Xuejing Yang
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Huijing Feng
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Jonghwa Kim
- Department of Pharmaceutical EngineeringWoosuk UniversityWanjuJeonbukSouthKorea
| | - Gang Ti
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Lin Wang
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Kun Wang
- Department of Pharmaceutical EngineeringWoosuk UniversityWanjuJeonbukSouthKorea
| | - Dong Song
- Cancer CenterShanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuan030032China
- Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
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Ivers JD, Puvvada N, Quick CM, Rajaram N. Investigating the relationship between hypoxia, hypoxia-inducible factor 1, and the optical redox ratio in response to radiation therapy. BIOPHOTONICS DISCOVERY 2024; 1:015003. [PMID: 40109884 PMCID: PMC11922545 DOI: 10.1117/1.bios.1.1.015003] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
Significance Radiation resistance is a major contributor to cancer treatment failure and is likely driven by multiple pathways. Multivariate visualization that preserves the spatial co-localization of factors could aid in understanding mechanisms of resistance and identifying biomarkers of response. Aim We aim to investigate the spatial and temporal relationship between hypoxia, hypoxia-inducible factor 1 (HIF-1α), and metabolism in response to radiation therapy in two cell lines of known radiation resistance and sensitivity. Approach Two-photon excited fluorescence and fluorescence lifetime imaging microscopy were used to quantify the optical redox ratio (ORR) and NAD(P)H fluorescent lifetime and bound fraction in frozen tumor sections and co-registered with immunohistochemical stain-based imaging of hypoxic fraction and HIF-1α. Results Histogram analysis of hypoxia, HIF-1α, and ORR revealed an increase in the ORR in regions of low hypoxia and high HIF-1α, indicating that the stabilization of HIF-1α is likely due to an increase in reactive oxygen species following radiation therapy. In addition, the bound NAD(P)H fraction was higher in regions with a low ORR in resistant tumors following radiation, suggesting an increase in fatty acid synthesis. Conclusions A multivariate histogram approach can reveal hidden trends not observed in bulk analysis of tumor images and may be useful in understanding biomarkers and mechanisms of radiation resistance.
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Affiliation(s)
- Jesse D Ivers
- University of Arkansas, Department of Biomedical Engineering, Fayetteville, Arkansas, United States
| | - Nagavenkatasai Puvvada
- University of Arkansas, Department of Biomedical Engineering, Fayetteville, Arkansas, United States
| | - Charles M Quick
- University of Arkansas for Medical Sciences, Department of Pathology, Little Rock, Arkansas, United States
| | - Narasimhan Rajaram
- University of Arkansas, Department of Biomedical Engineering, Fayetteville, Arkansas, United States
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7
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Shah V, Panchal V, Shah A, Vyas B, Agrawal S, Bharadwaj S. Immune checkpoint inhibitors in metastatic melanoma therapy (Review). MEDICINE INTERNATIONAL 2024; 4:13. [PMID: 38410760 PMCID: PMC10895472 DOI: 10.3892/mi.2024.137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 01/26/2024] [Indexed: 02/28/2024]
Abstract
An increase in the incidence of melanoma has been observed in recent decades, which poses a significant challenge due to its poor prognosis in the advanced and metastatic stages. Previously, chemotherapy and high doses of interleukin-2 were available treatments for melanoma; however, they offered limited survival benefits and were associated with severe toxicities. The treatment of metastatic melanoma has been transformed by new developments in immunotherapy. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that target cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligand, PDL-1, have emerged as promising therapeutic options. Commonly used ICIs, such as ipilimumab, nivolumab and pembrolizumab, have been found to be associated with an improved median overall survival, recurrence-free survival and response rates compared to traditional chemotherapies. Combination therapies involving different types of ICIs, such as anti-PD1 with anti-CTLA-4, have further enhanced the overall survival and response rates by targeting various phases of T-cell activation. Additionally, the development of novel biomarkers has facilitated the assessment of responses to ICI therapy, with tissue and serum-based prognostic and predictive biomarkers now available. The increased response observed with ICIs also provides potential for immune-related adverse effects on various organ systems. Further research is required to evaluate the efficacy and safety of various combinations of ICIs, while ongoing clinical trials explore the potential of newer ICIs. Concerns regarding the development of resistance to ICIs also warrant attention. The present review summarizes and discusses the advent of ICIs with a marked significant breakthrough in the treatment of metastatic melanoma, providing improved outcomes compared to traditional therapies.
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Affiliation(s)
- Vedant Shah
- Department of Medicine, Smt. N.H.L. Municipal Medical College and Sardar Vallabhbhai Patel Institute of Medical Sciences and Research (SVPISMR), Ahmedabad, Gujarat 380058, India
| | - Viraj Panchal
- Department of Medicine, Smt. N.H.L. Municipal Medical College and Sardar Vallabhbhai Patel Institute of Medical Sciences and Research (SVPISMR), Ahmedabad, Gujarat 380058, India
| | - Abhi Shah
- Department of Medicine, Smt. N.H.L. Municipal Medical College and Sardar Vallabhbhai Patel Institute of Medical Sciences and Research (SVPISMR), Ahmedabad, Gujarat 380058, India
| | - Bhavya Vyas
- Department of Medicine, Smt. N.H.L. Municipal Medical College and Sardar Vallabhbhai Patel Institute of Medical Sciences and Research (SVPISMR), Ahmedabad, Gujarat 380058, India
| | - Siddharth Agrawal
- Department of Medicine, Smt. N.H.L. Municipal Medical College and Sardar Vallabhbhai Patel Institute of Medical Sciences and Research (SVPISMR), Ahmedabad, Gujarat 380058, India
| | - Sanket Bharadwaj
- Department of Medicine, Smt. N.H.L. Municipal Medical College and Sardar Vallabhbhai Patel Institute of Medical Sciences and Research (SVPISMR), Ahmedabad, Gujarat 380058, India
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8
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Hine C, Patel AK, Ponti AK. Diet-Modifiable Redox Alterations in Ageing and Cancer. Subcell Biochem 2024; 107:129-172. [PMID: 39693023 PMCID: PMC11753504 DOI: 10.1007/978-3-031-66768-8_7] [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] [Indexed: 12/19/2024]
Abstract
With ageing comes some of life's best and worst moments. Those lucky enough to live out into the seventh, eighth, and nineth decades and perhaps beyond have more opportunities to experience the wonders and joys of the world. As the world's population shifts towards more and more of these individuals, this is something to be celebrated. However, it is not without negative consequences. Advanced age also ushers in health decline and the burden of non-communicable diseases such as cancer, heart disease, stroke, and organ function decay. Thus, alleviating or at least dampening the severity of ageing as a whole, as well as these individual age-related disorders will enable the improvement in lifespan and healthspan. In the following chapter, we delve into hypothesised causes of ageing and experimental interventions that can be taken to slow their progression. We also highlight cellular and subcellular mechanisms of ageing with a focus on protein thiol oxidation and posttranslational modifications that impact cellular homeostasis and the advent and progression of ageing-related cancers. By having a better understanding of the mechanisms of ageing, we can hopefully develop effective, safe, and efficient therapeutic modalities that can be used prophylactically and/or concurrent to the onset of ageing.
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Affiliation(s)
- Christopher Hine
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA.
| | - Anand Kumar Patel
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
- Cardiovascular Genetics Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
| | - András K Ponti
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA
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9
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Hazem RM, Aboslema RF, Mehanna ET, Kishk SM, Elsayed M, El-Sayed NM. Antitumor effect of trimetazidine in a model of solid Ehrlich carcinoma is mediated by inhibition of glycolytic pathway and AKT signaling. Chem Biol Interact 2023; 383:110672. [PMID: 37591408 DOI: 10.1016/j.cbi.2023.110672] [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: 05/25/2023] [Revised: 07/18/2023] [Accepted: 08/12/2023] [Indexed: 08/19/2023]
Abstract
Disturbance in glucose metabolism was proposed to be a pathogenetic mechanism of breast cancer. Trimetazidine (TMZ) inhibits β-oxidation of fatty acids through blocking the activity of 3-ketoacylCoA thiolase enzyme, leading to enhancement of glucose oxidation and metabolic respiration. The present study aimed to examine the cytotoxic effect of TMZ in both in vivo and in vitro models of breast cancer, focusing on its impact on the expression of some glycolytic enzymes and AKT signaling. The cytotoxic effect of TMZ was screened against breast (MCF-7) cancer cell line at different concentrations [0.01-100 μM]. In vivo, graded doses (10, 20, 30 mg/kg) of TMZ were tested against solid Ehrlich carcinoma (SEC) in mice. Tumor tissues were isolated for assessment of the expression of glucose transporter-1 (GLUT-1) and glycolytic enzymes by quantitative PCR. The protein expression of AKT and cellular myelocytomatosis (c-Myc) was determined by western blotting, while p53 expression was evaluated by immunohistochemistry. Molecular docking study of TMZ effect on AKT and c-Myc was performed using Auto-Dock Vina docking program. TMZ showed a cytotoxic action against MCF-7 cells, having IC50 value of 2.95 μM. In vivo, TMZ reduced tumor weight, downregulated the expression of glycolytic enzymes, suppressed AKT signaling, but increased p53 expression. Molecular docking and in silico studies proposed that TMZ is an AKT and c-Myc selective inhibitor. In conclusion, TMZ demonstrated a viable approach to suppress tumor proliferation in biological models of breast cancer.
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Affiliation(s)
- Reem M Hazem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Rasha F Aboslema
- The Egyptian Ministry of Health and Population, Port Said, Egypt
| | - Eman T Mehanna
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt.
| | - Safaa M Kishk
- Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Mohammed Elsayed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Norhan M El-Sayed
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
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10
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Zhou TJ, Wan X, Zhang MM, Liu DM, Huang LL, Xing L, Wang Y, Jiang HL. Tumor microenvironment-initiated lipid redox cycling for efficient triple-negative breast cancer therapy. Biomaterials 2023; 300:122205. [PMID: 37348324 DOI: 10.1016/j.biomaterials.2023.122205] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 05/09/2023] [Accepted: 06/09/2023] [Indexed: 06/24/2023]
Abstract
The use of overwhelming reactive oxygen species (ROS) attack has shown great potential for treating aggressive malignancies; however, targeting this process for further applications is greatly hindered by inefficiency and low selectivity. Here, a novel strategy for ROS explosion induced by tumor microenvironment-initiated lipid redox cycling was proposed, which was developed by using soybean phosphatidylcholine (SPC) to encapsulate lactate oxidase (LOX) and sorafenib (SRF) self-assembled nanoparticles (NPs), named LOX/SRF@Lip. SPC is not only the delivery carrier but an unsaturated lipid supplement for ROS explosion. And LOX catalyzes excessive intratumoral lactate to promote the accumulation of large amounts of H2O2. Then, H2O2 reacts with excessive endogenous iron ions to generate amounts of hydroxyl radical for the initiation of SPC peroxidation. Once started, the reaction will proceed via propagation to form new lipid peroxides (LPO), resulting to devastating LPO explosion and widespread oxidative damage in tumor cells. Furthermore, SRF makes contribution to mass LPO accumulation by inhibiting LPO elimination. Compared to normal tissue, tumor tissue has higher levels of lactate and iron ions. Therefore, LOX/SRF@Lip shows low toxicity in normal tissues, but generates efficient inhibition on tumor proliferation and metastasis, enabling excellent and safe tumor-specific therapy. This work offers new ideas on how to magnify anticancer effect of ROS through rational nanosystem design and tumor-specific microenvironment utilization.
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Affiliation(s)
- Tian-Jiao Zhou
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China
| | - Xing Wan
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China
| | - Meng-Meng Zhang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China
| | - Dan-Meng Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China
| | - Li-Ling Huang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009, PR China; NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, 210009, PR China
| | - Yi Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China.
| | - Hu-Lin Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, PR China; Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009, PR China; NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, China Pharmaceutical University, 210009, PR China.
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11
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Vanstraelen S, Jones DR, Rocco G. Breathprinting analysis and biomimetic sensor technology to detect lung cancer. J Thorac Cardiovasc Surg 2023; 166:357-361.e1. [PMID: 36997463 DOI: 10.1016/j.jtcvs.2023.02.029] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/15/2023] [Accepted: 02/28/2023] [Indexed: 03/11/2023]
Affiliation(s)
- Stijn Vanstraelen
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - David R Jones
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Gaetano Rocco
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY.
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12
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Reynolds L, Luo Z, Singh K. Diabetic complications and prospective immunotherapy. Front Immunol 2023; 14:1219598. [PMID: 37483613 PMCID: PMC10360133 DOI: 10.3389/fimmu.2023.1219598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/22/2023] [Indexed: 07/25/2023] Open
Abstract
The incidence of Diabetes Mellitus is increasing globally. Individuals who have been burdened with diabetes for many years often develop complications as a result of hyperglycemia. More and more research is being conducted highlighting inflammation as an important factor in disease progression. In all kinds of diabetes, hyperglycemia leads to activation of alternative glucose metabolic pathways, resulting in problematic by-products including reactive oxygen species and advanced glycation end products. This review takes a look into the pathogenesis of three specific diabetic complications; retinopathy, nephropathy and neuropathy as well as their current treatment options. By considering recent research papers investigating the effects of immunotherapy on relevant conditions in animal models, multiple strategies are suggested for future treatment and prevention of diabetic complications with an emphasis on molecular targets associated with the inflammation.
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13
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Li Y, Han X, Lin Z, Wang C, Fu Z, Sun Q, Li C. G6PD activation in TNBC cells induces macrophage recruitment and M2 polarization to promote tumor progression. Cell Mol Life Sci 2023; 80:165. [PMID: 37237244 PMCID: PMC11073185 DOI: 10.1007/s00018-023-04810-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/28/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023]
Abstract
Glucose-6-phosphate dehydrogenase (G6PD) is involved in triple-negative breast cancer (TNBC) progression. Metabolic crosstalk between cancer cells and tumor-associated macrophages mediates tumor progression in TNBC. Molecular biological methods were applied to clarify the mechanism of the crosstalk between TNBC cells and M2 macrophages. In the present study, we verified that G6PD overexpression drives M2 macrophage polarization by directly combining with phospho-STAT1 and upregulating CCL2 and TGF-β1 secretion in TNBC cells. In turn, M2-like TAMs activated TNBC cells through IL-10 secretion, providing feedback to upregulate G6PD and promote TNBC cell migration and proliferation in vitro. Furthermore, we found that 6-AN (a specific inhibitor of G6PD) not only suppressed the cancer-driven polarization of macrophages toward the M2 phenotype but also inhibited the inherent M2 polarization of macrophages. Targeting the G6PD-regulated pentose phosphate pathway restrained TNBC progression and M2-type polarization of macrophages in vitro and in vivo.
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Affiliation(s)
- Yin Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, No.38 Tongyan Road, Jinnan District, Tianjin, 300350, People's Republic of China
| | - Xiao Han
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, No.38 Tongyan Road, Jinnan District, Tianjin, 300350, People's Republic of China
| | - Zhoujun Lin
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, No.38 Tongyan Road, Jinnan District, Tianjin, 300350, People's Republic of China
| | - Changjun Wang
- Department of Breast Surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
| | - Zhenkun Fu
- Department of Immunology, Wu Lien-Teh Institute, Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University & Heilongjiang Academy of Medical Science, No.157 Baojian Street, Nangang District, Harbin, 150086, People's Republic of China.
| | - Qiang Sun
- Department of Breast Surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
| | - Chenggang Li
- State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, No.38 Tongyan Road, Jinnan District, Tianjin, 300350, People's Republic of China.
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14
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A reduced model of cell metabolism to revisit the glycolysis-OXPHOS relationship in the deregulated tumor microenvironment. J Theor Biol 2023; 562:111434. [PMID: 36739944 DOI: 10.1016/j.jtbi.2023.111434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 01/24/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023]
Abstract
Cancer cells metabolism focuses the interest of the cancer research community. Although this process is intensely studied experimentally, there are very few theoretical models that address this issue. One of the main reasons is the extraordinary complexity of the metabolism that involves numerous interdependent regulatory networks which makes the computational recreation of this complexity illusory. In this study we propose a reduced model of the metabolism which focuses on the interrelation of the three main energy metabolites which are oxygen, glucose and lactate in order to better understand the dynamics of the core system of the glycolysis-OXPHOS relationship. So simple as it is, the model highlights the main rules allowing the cell to dynamically adapt its metabolism to its changing environment. It also makes it possible to address this impact at the tissue scale. The simulations carried out in a spheroid show non-trivial spatial heterogeneity of energy metabolism. It further suggests that the metabolic features that are commonly attributed to cancer cells are not necessarily due to an intrinsic abnormality of the cells. They can emerge spontaneously due to the deregulated over-acidic environment.
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15
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Ou ZY, Wang K, Shen WW, Deng G, Xu YY, Wang LF, Zai ZY, Ling YA, Zhang T, Peng XQ, Chen FH. Oncogenic FLT3 internal tandem duplication activates E2F1 to regulate purine metabolism in acute myeloid leukaemia. Biochem Pharmacol 2023; 210:115458. [PMID: 36803956 DOI: 10.1016/j.bcp.2023.115458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 01/28/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023]
Abstract
Oncogene FLT3 internal tandem duplication (FLT3-ITD) mutation accounts for 30 % of acute myeloid leukaemia (AML) cases and induces transformation. Previously, we found that E2F transcription factor 1 (E2F1) was involved in AML cell differentiation. Here, we reported that E2F1 expression was aberrantly upregulated in AML patients, especially in AML patients carrying FLT3-ITD. E2F1 knockdown inhibited cell proliferation and increased cell sensitivity to chemotherapy in cultured FLT3-ITD-positive AML cells. E2F1-depleted FLT3-ITD+ AML cells lost their malignancy as shown by the reduced leukaemia burden and prolonged survival in NOD-PrkdcscidIl2rgem1/Smoc mice receiving xenografts. Additionally, FLT3-ITD-driven transformation of human CD34+ hematopoietic stem and progenitor cells was counteracted by E2F1 knockdown. Mechanistically, FLT3-ITD enhanced the expression and nuclear accumulation of E2F1 in AML cells. Further study using chromatin immunoprecipitation-sequencing and metabolomics analyses revealed that ectopic FLT3-ITD promoted the recruitment of E2F1 on genes encoding key enzymatic regulators of purine metabolism and thus supported AML cell proliferation. Together, this study demonstrates that E2F1-activated purine metabolism is a critical downstream process of FLT3-ITD in AML and a potential target for FLT3-ITD+ AML patients.
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Affiliation(s)
- Zi-Yao Ou
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Ke Wang
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Wen-Wen Shen
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Ge Deng
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Ya-Yun Xu
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Long-Fei Wang
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Zhuo-Yan Zai
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yi-An Ling
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Tao Zhang
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Xiao-Qing Peng
- Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
| | - Fei-Hu Chen
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Medical University, Hefei, Anhui, China; Anhui Laboratory of Inflammatory and Immune Disease, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China.
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16
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Missiaen R, Lesner NP, Simon MC. HIF: a master regulator of nutrient availability and metabolic cross-talk in the tumor microenvironment. EMBO J 2023; 42:e112067. [PMID: 36808622 PMCID: PMC10015374 DOI: 10.15252/embj.2022112067] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 02/22/2023] Open
Abstract
A role for hypoxia-inducible factors (HIFs) in hypoxia-dependent regulation of tumor cell metabolism has been thoroughly investigated and covered in reviews. However, there is limited information available regarding HIF-dependent regulation of nutrient fates in tumor and stromal cells. Tumor and stromal cells may generate nutrients necessary for function (metabolic symbiosis) or deplete nutrients resulting in possible competition between tumor cells and immune cells, a result of altered nutrient fates. HIF and nutrients in the tumor microenvironment (TME) affect stromal and immune cell metabolism in addition to intrinsic tumor cell metabolism. HIF-dependent metabolic regulation will inevitably result in the accumulation or depletion of essential metabolites in the TME. In response, various cell types in the TME will respond to these hypoxia-dependent alterations by activating HIF-dependent transcription to alter nutrient import, export, and utilization. In recent years, the concept of metabolic competition has been proposed for critical substrates, including glucose, lactate, glutamine, arginine, and tryptophan. In this review, we discuss how HIF-mediated mechanisms control nutrient sensing and availability in the TME, the competition for nutrients, and the metabolic cross-talk between tumor and stromal cells.
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Affiliation(s)
- Rindert Missiaen
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicholas P Lesner
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA
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17
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Moreno-Sánchez R, Robledo-Cadena DX, Pacheco-Velázquez SC, Vargas Navarro JL, Padilla-Flores JA, Rodríguez-Enríquez S. Estimation of energy pathway fluxes in cancer cells - Beyond the Warburg effect. Arch Biochem Biophys 2023; 739:109559. [PMID: 36906097 DOI: 10.1016/j.abb.2023.109559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 02/15/2023] [Accepted: 03/04/2023] [Indexed: 03/11/2023]
Abstract
Glycolytic and respiratory fluxes were analyzed in cancer and non-cancer cells. The steady-state fluxes in energy metabolism were used to estimate the contributions of aerobic glycolytic and oxidative phosphorylation (OxPhos) pathways to the cellular ATP supply. The rate of lactate production - corrected for the fraction generated by glutaminolysis - is proposed as the appropriate way to estimate glycolytic flux. In general, the glycolytic rates estimated for cancer cells are higher than those found in non-cancer cells, as originally observed by Otto Warburg. The rate of basal or endogenous cellular O2 consumption corrected for non-ATP synthesizing O2 consumption, measured after inhibition by oligomycin (a specific, potent and permeable ATP synthase inhibitor), has been proposed as the appropriate way to estimate mitochondrial ATP synthesis-linked O2 flux or net OxPhos flux in living cells. Detecting non-negligible oligomycin-sensitive O2 consumption rates in cancer cells has revealed that the mitochondrial function is not impaired, as claimed by the Warburg effect. Furthermore, when calculating the relative contributions to cellular ATP supply, under a variety of environmental conditions and for different types of cancer cells, it was found that OxPhos pathway was the main ATP provider over glycolysis. Hence, OxPhos pathway targeting can be successfully used to block in cancer cells ATP-dependent processes such as migration. These observations may guide the re-design of novel targeted therapies.
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Affiliation(s)
- Rafael Moreno-Sánchez
- Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Carrera de Biología, Laboratorio de Control Metabólico, Los Reyes Ixtacala, Hab. Los Reyes Ixtacala Barrio de los Árboles/Barrio de los Héroes, Tlalnepantla, 54090, Mexico.
| | | | | | - Jorge Luis Vargas Navarro
- Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Carrera de Biología, Laboratorio de Control Metabólico, Los Reyes Ixtacala, Hab. Los Reyes Ixtacala Barrio de los Árboles/Barrio de los Héroes, Tlalnepantla, 54090, Mexico
| | - Joaquín Alberto Padilla-Flores
- Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Carrera de Biología, Laboratorio de Control Metabólico, Los Reyes Ixtacala, Hab. Los Reyes Ixtacala Barrio de los Árboles/Barrio de los Héroes, Tlalnepantla, 54090, Mexico
| | - Sara Rodríguez-Enríquez
- Instituto Nacional de Cardiología, Departamento de Bioquímica, Ciudad de México, 14080, Mexico; Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Carrera de Medicina, Laboratorio de Control Metabólico, Los Reyes Ixtacala, Hab. Los Reyes Ixtacala Barrio de los Árboles/Barrio de los Héroes, Tlalnepantla, 54090, Mexico.
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18
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Powell BH, Turchinovich A, Wang Y, Gololobova O, Buschmann D, Zeiger MA, Umbricht CB, Witwer KW. miR-210 Expression Is Strongly Hypoxia-Induced in Anaplastic Thyroid Cancer Cell Lines and Is Associated with Extracellular Vesicles and Argonaute-2. Int J Mol Sci 2023; 24:4507. [PMID: 36901936 PMCID: PMC10002857 DOI: 10.3390/ijms24054507] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/06/2023] [Accepted: 02/10/2023] [Indexed: 03/03/2023] Open
Abstract
Hypoxia, or low oxygen tension, is frequently found in highly proliferative solid tumors such as anaplastic thyroid carcinoma (ATC) and is believed to promote resistance to chemotherapy and radiation. Identifying hypoxic cells for targeted therapy may thus be an effective approach to treating aggressive cancers. Here, we explore the potential of the well-known hypoxia-responsive microRNA (miRNA) miR-210-3p as a cellular and extracellular biological marker of hypoxia. We compare miRNA expression across several ATC and papillary thyroid cancer (PTC) cell lines. In the ATC cell line SW1736, miR-210-3p expression levels indicate hypoxia during exposure to low oxygen conditions (2% O2). Furthermore, when released by SW1736 cells into the extracellular space, miR-210-3p is associated with RNA carriers such as extracellular vesicles (EVs) and Argonaute-2 (AGO2), making it a potential extracellular marker for hypoxia.
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Affiliation(s)
- Bonita H. Powell
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Andrey Turchinovich
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Heidelberg Biolabs GmbH, 69120 Heidelberg, Germany
| | - Yongchun Wang
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Olesia Gololobova
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Dominik Buschmann
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Martha A. Zeiger
- Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA
| | - Christopher B. Umbricht
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Kenneth W. Witwer
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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19
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Dias AS, Almeida CR, Helguero LA, Duarte IF. Metabolic Reprogramming of Breast Tumor-Educated Macrophages Revealed by NMR Metabolomics. Cancers (Basel) 2023; 15:cancers15041211. [PMID: 36831553 PMCID: PMC9954003 DOI: 10.3390/cancers15041211] [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: 12/15/2022] [Revised: 02/03/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
The metabolic crosstalk between tumor cells and tumor-associated macrophages (TAMs) has emerged as a critical contributor to tumor development and progression. In breast cancer (BC), the abundance of immune-suppressive TAMs positively correlates with poor prognosis. However, little is known about how TAMs reprogram their metabolism in the BC microenvironment. In this work, we have assessed the metabolic and phenotypic impact of incubating THP-1-derived macrophages in conditioned media (CM) from two BC cell lines cultured in normoxia/hypoxia: MDA-MB-231 cells (highly metastatic, triple-negative BC), and MCF-7 cells (less aggressive, luminal BC). The resulting tumor-educated macrophages (TEM) displayed prominent differences in their metabolic activity and composition, compared to control cells (M0), as assessed by exo- and endometabolomics. In particular, TEM turned to the utilization of extracellular pyruvate, alanine, and branched chain keto acids (BCKA), while exhibiting alterations in metabolites associated with several intracellular pathways, including polyamines catabolism (MDA-TEM), collagen degradation (mainly MCF-TEM), adenosine accumulation (mainly MDA-TEM) and lipid metabolism. Interestingly, following a second-stage incubation in fresh RPMI medium, TEM still displayed several metabolic differences compared to M0, indicating persistent reprogramming. Overall, this work provided new insights into the metabolic plasticity of TEM, revealing potentially important nutritional exchanges and immunoregulatory metabolites in the BC TME.
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Affiliation(s)
- Ana S. Dias
- CICECO—Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
- iBiMED—Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Catarina R. Almeida
- iBiMED—Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Luisa A. Helguero
- iBiMED—Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Iola F. Duarte
- CICECO—Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
- Correspondence: ; Tel.: +351-234-401-418
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20
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Kenney RM, Lee MC, Boyce MW, Sitte ZR, Lockett MR. Cellular Invasion Assay for the Real-Time Tracking of Individual Cells in Spheroid or Tumor-like Mimics. Anal Chem 2023; 95:3054-3061. [PMID: 36701161 PMCID: PMC10007898 DOI: 10.1021/acs.analchem.2c05201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Cellular invasion is the gateway to metastasis, with cells moving from a primary tumor into neighboring regions of healthy tissue. Invasion assays provide a tractable experimental platform to quantitatively assess cellular movement in the presence of potential chemokines or inhibitors. Many such assays involve cellular movement from high cell densities to cell-free regions. To improve the physiological relevance of such assays, we developed an assay format to track cellular movement throughout a uniform density of cells. This assay format imparts diffusion-dominated environments along the channel, resulting in oxygen and nutrient gradients found in spheroids or poorly vascularized tumors. By incorporating oxygen- and pH-sensing films, we quantified spatial and temporal changes in the extracellular environment while simultaneously tracking the movement of a subset of cells engineered to express fluorescent proteins constitutively. Our results show the successful invasion into neighboring tissues likely arises from a small population with a highly invasive phenotype. These highly invasive cells continued to move throughout the 48 h experiment, suggesting they have stem-like or persister properties. Surprisingly, the distance these persister cells invaded was unaffected by the density of cells in the channel or the presence or absence of an oxygen gradient. While these datasets cannot determine if the invasive cells are inherent to the population or if diffusion-dominated environments promote them, they highlight the need for further study.
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Affiliation(s)
- Rachael M. Kenney
- Department of Chemistry, University of North Carolina at Chapel Hill, 125 South Road, Chapel Hill, NC 27599-3290
| | - Maggie C. Lee
- Department of Chemistry, University of North Carolina at Chapel Hill, 125 South Road, Chapel Hill, NC 27599-3290
| | - Matthew W. Boyce
- Department of Chemistry, University of North Carolina at Chapel Hill, 125 South Road, Chapel Hill, NC 27599-3290
| | - Zachary R. Sitte
- Department of Chemistry, University of North Carolina at Chapel Hill, 125 South Road, Chapel Hill, NC 27599-3290
| | - Matthew R. Lockett
- Department of Chemistry, University of North Carolina at Chapel Hill, 125 South Road, Chapel Hill, NC 27599-3290
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, NC 27599-7295
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21
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Samra YA, Zaidi Y, Rajpurohit P, Raghavan R, Cai L, Kaddour-Djebbar I, Tawfik A. Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration. Int J Mol Sci 2023; 24:ijms24021071. [PMID: 36674587 PMCID: PMC9865636 DOI: 10.3390/ijms24021071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/31/2022] [Accepted: 01/02/2023] [Indexed: 01/09/2023] Open
Abstract
Age-related macular degeneration (AMD) is a major cause of blindness. Recent studies have reported impaired glycolysis in AMD patients with a high lactate/pyruvate ratio. Elevated homocysteine (Hcy) (Hyperhomocysteinemia, HHcy) was observed in several clinical studies, reporting an association between HHcy and AMD. We established the effect of HHcy on barrier function, retinal pigment epithelium (RPE) structure, and induced choroidal neovascularization (CNV) in mice. We hypothesize that HHcy contributes to AMD by inducing a metabolic switch in the mitochondria, in which cells predominantly produce energy by the high rate of glycolysis, or "Warburg", effect. Increased glycolysis results in an increased production of lactate, cellular acidity, activation of angiogenesis, RPE barrier dysfunction, and CNV. Evaluation of cellular energy production under HHcy was assessed by seahorse analysis, immunofluorescence, and western blot experiments. The seahorse analysis evaluated the extracellular acidification rate (ECAR) as indicative of glycolysis. HHcy showed a significant increase in ECAR both in vivo using (Cystathionine β-synthase) cbs+/- and cbs-/- mice retinas and in vitro (Hcy-treated ARPE-19) compared to wild-type mice and RPE cells. Moreover, HHcy up-regulated glycolytic enzyme (Glucose transporter-1 (GlUT-1), lactate dehydrogenase (LDH), and hexokinase 1 (HK1)) in Hcy-treated ARPE-19 and primary RPE cells isolated from cbs+/+, cbs+/-, and cbs-/- mice retinas. Inhibition of GLUT-1 or blocking of N-methyl-D-aspartate receptors (NMDAR) reduced glycolysis in Hcy-treated RPE and improved albumin leakage and CNV induction in Hcy-injected mice eyes. The current study suggests that HHcy causes a metabolic switch in the RPE cells from mitochondrial respiration to glycolysis during AMD and confirms the involvement of NMDAR in this process. Therefore, targeting Glycolysis or NMDAR could be a novel therapeutic target for AMD.
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Affiliation(s)
- Yara A. Samra
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Yusra Zaidi
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Pragya Rajpurohit
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Raju Raghavan
- Department of Pharmacology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Lun Cai
- Department of Pharmacology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Ismail Kaddour-Djebbar
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA
| | - Amany Tawfik
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA
- Eye Research Institute, Oakland University, Rochester, MI 48309-4479, USA
- Eye Research Center (OUWB)/ERC, William Beaumont School of Medicine, Royal Oak, MI 48309-4479, USA
- Correspondence: ; Tel.: +1-248-370-2398; Fax: +1-248-370-4211
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22
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Lou K, Feng S, Luo H, Zou J, Zhang G, Zou X. Extracellular vesicles derived from macrophages: Current applications and prospects in tumors. Front Bioeng Biotechnol 2022; 10:1097074. [PMID: 36588947 PMCID: PMC9797603 DOI: 10.3389/fbioe.2022.1097074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022] Open
Abstract
Macrophages (Mφs) are significant innate immune cells that perform a variety of tasks in response to different pathogens or stimuli. They are widely engaged in the pathological processes of various diseases and can contribute to tumorigenesis, progression and metastasis by regulating the tumor microenvironment and cancer cells. They are also the basis of chemoresistance. In turn, the tumor microenvironment and the metabolism of cancer cells can limit the differentiation, polarization, mobilization and the ability of Mφs to initiate an effective anti-tumor response. Extracellular vesicles (EVs) are small vesicles released by live cells that serve as crucial mediators of intercellular cell communication as well as a potential promising drug carrier. A growing number of studies have demonstrated that Mφs-EVs are not only important mediators in the pathological processes of various diseases such as inflammatory disorders, fibrosis and cancer, but also show significant potential in immunological modulation, cancer therapy, infectious defense and tissue repair. These natural nanoparticles (NPs) derived from Mφs are believed to be pleiotropic, stable, biocompatible and low immunogenic, providing novel alternatives for cancer treatment. This review provides an update on the pathological and therapeutic roles of Mφs-EVs in cancer, as well as their potential clinical applications and prospects.
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Affiliation(s)
- Kecheng Lou
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Shangzhi Feng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Hui Luo
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China,Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junrong Zou
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Institute of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Jiangxi Engineering Technology Research Center of Calculi Prevention, Ganzhou, Jiangxi, China
| | - Guoxi Zhang
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Institute of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Jiangxi Engineering Technology Research Center of Calculi Prevention, Ganzhou, Jiangxi, China
| | - Xiaofeng Zou
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Institute of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China,Jiangxi Engineering Technology Research Center of Calculi Prevention, Ganzhou, Jiangxi, China,*Correspondence: Xiaofeng Zou,
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23
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Hargadon KM, Goodloe TB, Lloyd ND. Oncogenic functions of the FOXC2 transcription factor: a hallmarks of cancer perspective. Cancer Metastasis Rev 2022; 41:833-852. [PMID: 35701636 DOI: 10.1007/s10555-022-10045-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/06/2022] [Indexed: 01/25/2023]
Abstract
Epigenetic regulation of gene expression is a fundamental determinant of molecular and cellular function, and epigenetic reprogramming in the context of cancer has emerged as one of the key enabling characteristics associated with acquisition of the core hallmarks of this disease. As such, there has been renewed interest in studying the role of transcription factors as epigenetic regulators of gene expression in cancer. In this review, we discuss the current state of knowledge surrounding the oncogenic functions of FOXC2, a transcription factor that frequently becomes dysregulated in a variety of cancer types. In addition to highlighting the clinical impact of aberrant FOXC2 activity in cancer, we discuss mechanisms by which this transcription factor becomes dysregulated in both tumor and tumor-associated cells, placing particular emphasis on the ways in which FOXC2 promotes key hallmarks of cancer progression. Finally, we bring attention to important issues related to the oncogenic dysregulation of FOXC2 that must be addressed going forward in order to improve our understanding of FOXC2-mediated cancer progression and to guide prognostic and therapeutic applications of this knowledge in clinical settings.
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Affiliation(s)
- Kristian M Hargadon
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, 23943, USA.
| | - Travis B Goodloe
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, 23943, USA
| | - Nathaniel D Lloyd
- Hargadon Laboratory, Department of Biology, Hampden-Sydney College, Hampden-Sydney, VA, 23943, USA
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24
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Pacheco-Velázquez SC, Ortega-Mejía II, Vargas-Navarro JL, Padilla-Flores JA, Robledo-Cadena DX, Tapia-Martínez G, Peñalosa-Castro I, Aguilar-Ponce JL, Granados-Rivas JC, Moreno-Sánchez R, Rodríguez-Enríquez S. 17-β Estradiol up-regulates energy metabolic pathways, cellular proliferation and tumor invasiveness in ER+ breast cancer spheroids. Front Oncol 2022; 12:1018137. [PMID: 36419896 PMCID: PMC9676491 DOI: 10.3389/fonc.2022.1018137] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 10/18/2022] [Indexed: 09/08/2024] Open
Abstract
Several biological processes related to cancer malignancy are regulated by 17-β estradiol (E2) in ER+-breast cancer. To establish the role of E2 on the atypical cancer energy metabolism, a systematic study analyzing transcription factors, proteins, and fluxes associated with energy metabolism was undertaken in multicellular tumor spheroids (MCTS) from human ER+ MCF-7 breast cancer cells. At E2 physiological concentrations (10 and 100 nM for 24 h), both ERα and ERβ receptors, and their protein target pS2, increased by 0.6-3.5 times vs. non-treated MCTS, revealing an activated E2/ER axis. E2 also increased by 30-470% the content of several transcription factors associated to mitochondrial biogenesis and oxidative phosphorylation (OxPhos) (p53, PGC1-α) and glycolytic pathways (HIF1-α, c-MYC). Several OxPhos and glycolytic proteins (36-257%) as well as pathway fluxes (48-156%) significantly increased being OxPhos the principal ATP cellular supplier (>75%). As result of energy metabolism stimulation by E2, cancer cell migration and invasion processes and related proteins (SNAIL, FN, MM-9) contents augmented by 24-189% vs. non-treated MCTS. Celecoxib at 10 nM blocked OxPhos (60%) as well as MCTS growth, cell migration and invasiveness (>40%); whereas the glycolytic inhibitor iodoacetate (0.5 µM) and doxorubicin (70 nM) were innocuous. Our results show for the first time using a more physiological tridimensional cancer model, resembling the initial stages of solid tumors, that anti-mitochondrial therapy may be useful to deter hormone-dependent breast carcinomas.
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Affiliation(s)
| | | | | | | | | | | | - Ignacio Peñalosa-Castro
- Laboratorio de Control Metabólico, Carrera de Biología, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Los Reyes Ixtacala, Hab, Tlalnepantla, Mexico
| | | | - Juan Carlos Granados-Rivas
- Laboratorio de Control Metabólico, Carrera de Medicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Los Reyes Ixtacala, Hab, Tlalnepantla, Mexico
| | - Rafael Moreno-Sánchez
- Laboratorio de Control Metabólico, Carrera de Biología, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Los Reyes Ixtacala, Hab, Tlalnepantla, Mexico
| | - Sara Rodríguez-Enríquez
- Departamento de Bioquímica, Instituto Nacional de Cardiología, Ciudad de México, Mexico
- Laboratorio de Control Metabólico, Carrera de Medicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Los Reyes Ixtacala, Hab, Tlalnepantla, Mexico
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25
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Sodium Thiosulphate-Loaded Liposomes Control Hydrogen Sulphide Release and Retain Its Biological Properties in Hypoxia-like Environment. Antioxidants (Basel) 2022; 11:antiox11112092. [DOI: 10.3390/antiox11112092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 10/09/2022] [Accepted: 10/18/2022] [Indexed: 11/16/2022] Open
Abstract
Hypoxia, or insufficient oxygen availability is a common feature in the development of a myriad of cardiovascular-related conditions including ischemic disease. Hydrogen sulphide (H2S) donors, such as sodium thiosulphate (STS), are known for their cardioprotective properties. However, H2S due to its gaseous nature, is released and cleared rapidly, limiting its potential translation to clinical settings. For the first time, we developed and characterised liposome formulations encapsulating STS and explored their potential for modulating STS uptake, H2S release and the ability to retain pro-angiogenic and biological signals in a hypoxia-like environment mirroring oxygen insufficiency in vitro. Liposomes were prepared by varying lipid ratios and characterised for size, polydispersity and charge. STS liposomal encapsulation was confirmed by HPLC-UV detection and STS uptake and H2S release was assessed in vitro. To mimic hypoxia, cobalt chloride (CoCl2) was administered in conjunction with formulated and non-formulated STS, to explore pro-angiogenic and metabolic signals. Optimised liposomal formulation observed a liposome diameter of 146.42 ± 7.34 nm, a polydispersity of 0.22 ± 0.19, and charge of 3.02 ± 1.44 mV, resulting in 25% STS encapsulation. Maximum STS uptake (76.96 ± 3.08%) from liposome encapsulated STS was determined at 24 h. Co-exposure with CoCl2 and liposome encapsulated STS resulted in increased vascular endothelial growth factor mRNA as well as protein expression, enhanced wound closure and increased capillary-like formation. Finally, liposomal STS reversed metabolic switch induced by hypoxia by enhancing mitochondrial bioenergetics. These novel findings provide evidence of a feasible controlled-delivery system for STS, thus H2S, using liposome-based nanoparticles. Likewise, data suggests that in scenarios of hypoxia, liposomal STS is a good therapeutic candidate to sustain pro-angiogenic signals and retain metabolic functions that might be impaired by limited oxygen and nutrient availability.
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26
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Spinicci K, Jacquet P, Powathil G, Stéphanou A. Modeling the role of HIF in the regulation of metabolic key genes LDH and PDH: Emergence of Warburg phenotype. COMPUTATIONAL AND SYSTEMS ONCOLOGY 2022. [DOI: 10.1002/cso2.1040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Affiliation(s)
- Kévin Spinicci
- Université Grenoble Alpes CNRS UMR 5525, VetAgro Sup, Grenoble INP, TIMC Grenoble France
- Department of Mathematics Swansea University Swansea UK
| | - Pierre Jacquet
- Université Grenoble Alpes CNRS UMR 5525, VetAgro Sup, Grenoble INP, TIMC Grenoble France
| | | | - Angélique Stéphanou
- Université Grenoble Alpes CNRS UMR 5525, VetAgro Sup, Grenoble INP, TIMC Grenoble France
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27
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Fourie C, du Plessis M, Mills J, Engelbrecht AM. The effect of HIF-1α inhibition in breast cancer cells prior to doxorubicin treatment under conditions of normoxia and hypoxia. Exp Cell Res 2022; 419:113334. [PMID: 36044939 DOI: 10.1016/j.yexcr.2022.113334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND Oxygen deprivation is a key hallmark within solid tumours that contributes to breast-tumour pathophysiology. Under these conditions, neoplastic cells activate several genes, regulated by the HIF-1 transcription factor, which alters the tumour microenvironment to promote survival - including resistance to cell death in therapeutic attempts such as doxorubicin (Dox) treatment. METHODS We investigated HIF-1ɑ as a therapeutic target to sensitize breast cancer cells to Dox treatment. Under both normoxic (21% O2) and hypoxic (∼0.1% O2) conditions, the HIF-1 inhibitor, 2-methoxyestradiol (2-ME), was investigated as an adjuvant for its ability to alter MCF-7 cell viability, apoptosis, autophagy and molecular pathways which are often associated with increased cell survival. RESULTS Here we observed that an inverse relationship between HIF-1ɑ and apoptosis exists and that Dox promotes autophagy under hypoxic conditions. Although adjuvant therapy with 2-ME induced an antagonistic effect in breast cancer cells, upregulated HIF-1ɑ expression in a hypoxic environment promotes treatment resistance and this was attenuated once HIF-1ɑ gene expression was silenced. CONCLUSION Therefore, highlighting the identification of possible hypoxia-targeting therapies for breast cancer patients can be beneficial by promoting more favourable treatment responses.
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Affiliation(s)
- Carla Fourie
- Department of Physiological Sciences, Faculty of Science, University of Stellenbosch, Stellenbosch, 7600, South Africa.
| | - Manisha du Plessis
- Department of Physiological Sciences, Faculty of Science, University of Stellenbosch, Stellenbosch, 7600, South Africa
| | - Justin Mills
- Department of Physiological Sciences, Faculty of Science, University of Stellenbosch, Stellenbosch, 7600, South Africa
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences, Faculty of Science, University of Stellenbosch, Stellenbosch, 7600, South Africa; African Cancer Institute (ACI), Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
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28
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Sawai S, Wong PF, Ramasamy TS. Hypoxia-regulated microRNAs: the molecular drivers of tumor progression. Crit Rev Biochem Mol Biol 2022; 57:351-376. [PMID: 35900938 DOI: 10.1080/10409238.2022.2088684] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Hypoxia is a common feature of the tumor microenvironment (TME) of nearly all solid tumors, leading to therapeutic failure. The changes in stiffness of the extracellular matrix (ECM), pH gradients, and chemical balance that contribute to multiple cancer hallmarks are closely regulated by intratumoral oxygen tension via its primary mediators, hypoxia-inducible factors (HIFs). HIFs, especially HIF-1α, influence these changes in the TME by regulating vital cancer-associated signaling pathways and cellular processes including MAPK/ERK, NF-κB, STAT3, PI3K/Akt, Wnt, p53, and glycolysis. Interestingly, research has revealed the involvement of epigenetic regulation by hypoxia-regulated microRNAs (HRMs) of downstream target genes involved in these signaling. Through literature search and analysis, we identified 48 HRMs that have a functional role in the regulation of 5 key cellular processes: proliferation, metabolism, survival, invasion and migration, and immunoregulation in various cancers in hypoxic condition. Among these HRMs, 17 were identified to be directly associated with HIFs which include miR-135b, miR-145, miR-155, miR-181a, miR-182, miR-210, miR-224, miR-301a, and miR-675-5p as oncomiRNAs, and miR-100-5p, miR-138, miR-138-5p, miR-153, miR-22, miR-338-3p, miR-519d-3p, and miR-548an as tumor suppressor miRNAs. These HRMs serve as a potential lead in the development of miRNA-based targeted therapy for advanced solid tumors. Future development of combined HIF-targeted and miRNA-targeted therapy is possible, which requires comprehensive profiling of HIFs-HRMs regulatory network, and improved formula of the delivery vehicles to enhance the therapeutic kinetics of the targeted cancer therapy (TCT) moving forward.
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Affiliation(s)
- Sakunie Sawai
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Wilayah Persekutuan Kuala Lumpur, Malaysia
| | - Thamil Selvee Ramasamy
- Stem Cell Biology Laboratory, Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Wilayah Persekutuan Kuala Lumpur, Malaysia
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29
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Ma S, Zhao Y, Lee WC, Ong LT, Lee PL, Jiang Z, Oguz G, Niu Z, Liu M, Goh JY, Wang W, Bustos MA, Ehmsen S, Ramasamy A, Hoon DSB, Ditzel HJ, Tan EY, Chen Q, Yu Q. Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy. Nat Commun 2022; 13:4118. [PMID: 35840558 PMCID: PMC9287350 DOI: 10.1038/s41467-022-31764-9] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 07/01/2022] [Indexed: 12/12/2022] Open
Abstract
The hypoxic tumor microenvironment has been implicated in immune escape, but the underlying mechanism remains elusive. Using an in vitro culture system modeling human T cell dysfunction and exhaustion in triple-negative breast cancer (TNBC), we find that hypoxia suppresses immune effector gene expression, including in T and NK cells, resulting in immune effector cell dysfunction and resistance to immunotherapy. We demonstrate that hypoxia-induced factor 1α (HIF1α) interaction with HDAC1 and concurrent PRC2 dependency causes chromatin remolding resulting in epigenetic suppression of effector genes and subsequent immune dysfunction. Targeting HIF1α and the associated epigenetic machinery can reverse the immune effector dysfunction and overcome resistance to PD-1 blockade, as demonstrated both in vitro and in vivo using syngeneic and humanized mice models. These findings identify a HIF1α-mediated epigenetic mechanism in immune dysfunction and provide a potential strategy to overcome immune resistance in TNBC. Hypoxia can promote tumor escape from immune surveillance and immunotherapy. Here, the authors show that hypoxia induces T and NK cell dysfunction through HIF1α-mediated epigenetic suppression of effector gene expression, conferring resistance to anti-PD1 blockade in triple negative breast cancer models.
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Affiliation(s)
- Shijun Ma
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore
| | - Yue Zhao
- Institute of Molecular and Cellular Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore
| | - Wee Chyan Lee
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore
| | - Li-Teng Ong
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore
| | - Puay Leng Lee
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore
| | - Zemin Jiang
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore
| | - Gokce Oguz
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore
| | - Zhitong Niu
- The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China
| | - Min Liu
- Institute of Molecular and Cellular Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore
| | - Jian Yuan Goh
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore
| | - Wenyu Wang
- The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510655, China
| | - Matias A Bustos
- Department of Translational Molecular Medicine, Saint John's Cancer Institute, Providence Health System, Santa Monica, CA, 90404, USA
| | - Sidse Ehmsen
- Department of Oncology, Odense University Hospital, Odense, 5230, Denmark
| | - Adaikalavan Ramasamy
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore
| | - Dave S B Hoon
- Department of Translational Molecular Medicine, Saint John's Cancer Institute, Providence Health System, Santa Monica, CA, 90404, USA
| | - Henrik J Ditzel
- Department of Oncology, Odense University Hospital, Odense, 5230, Denmark.,Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, 5230, Denmark
| | - Ern Yu Tan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, 308433, Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cellular Biology, Agency for Science, Technology and Research (A*STAR), Singapore, 138673, Singapore.
| | - Qiang Yu
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, 138672, Singapore. .,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore. .,Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.
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30
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Barone A, d’Avanzo N, Cristiano MC, Paolino D, Fresta M. Macrophage-Derived Extracellular Vesicles: A Promising Tool for Personalized Cancer Therapy. Biomedicines 2022; 10:1252. [PMID: 35740274 PMCID: PMC9220135 DOI: 10.3390/biomedicines10061252] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/23/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
The incidence of cancer is increasing dramatically, affecting all ages of the population and reaching an ever higher worldwide mortality rate. The lack of therapies' efficacy is due to several factors such as a delay in diagnosis, tumor regrowth after surgical resection and the occurrence of multidrug resistance (MDR). Tumor-associated immune cells and the tumor microenvironment (TME) deeply affect the tumor's progression, leading to several physicochemical changes compared to physiological conditions. In this scenario, macrophages play a crucial role, participating both in tumor suppression or progression based on the polarization of onco-suppressive M1 or pro-oncogenic M2 phenotypes. Moreover, much evidence supports the pivotal role of macrophage-derived extracellular vesicles (EVs) as mediators in TME, because of their ability to shuttle the cell-cell and organ-cell communications, by delivering nucleic acids and proteins. EVs are lipid-based nanosystems with a broad size range distribution, which reflect a similar composition of native parent cells, thus providing a natural selectivity towards target sites. In this review, we discuss the impact of macrophage-derived EVs in the cancer's fate as well as their potential implications for the development of personalized anticancer nanomedicine.
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Affiliation(s)
- Antonella Barone
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro Campus Universitario-Germaneto, Viale Europa, 88100 Catanzaro, Italy; (A.B.); (M.C.C.)
| | - Nicola d’Avanzo
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini n.31, 66100 Chieti, Italy;
| | - Maria Chiara Cristiano
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro Campus Universitario-Germaneto, Viale Europa, 88100 Catanzaro, Italy; (A.B.); (M.C.C.)
| | - Donatella Paolino
- Department of Experimental and Clinical Medicine, University “Magna Græcia” of Catanzaro Campus Universitario-Germaneto, Viale Europa, 88100 Catanzaro, Italy; (A.B.); (M.C.C.)
| | - Massimo Fresta
- Department of Health Science, University “Magna Græcia” of Catanzaro Campus Universitario-Germaneto, Viale Europa, 88100 Catanzaro, Italy;
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31
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Ozlem Zurnaci F, Guzel M. The Effects of Increased Glucose Level and the Role of Glycolysis on SARS CoV-2 Infection. Mini Rev Med Chem 2022; 22:2344-2349. [DOI: 10.2174/1389557522666220318115350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/12/2021] [Accepted: 12/20/2021] [Indexed: 01/08/2023]
Abstract
Abstract:
Covid-19 has entered our lives for a long time as an infection with high mortality rates. Although the vaccination process has provided benefits, the death toll remains to be frightening worldwide. Therefore, drugs and combined therapies that can be used against Covid-19 infection are still being investigated. Most of these antiviral medications are investigational drug candidates which are still in clinical trials. In this context, holistic and different approaches for the treatment of Covid-19 including prophylactic use of natural medicines are under investigation and may offer potential treatment options due to the fact that this is still an unmet medical need in the world. Thus, inhibiting the increased glycolysis on Covid-19 infection with glycolysis inhibitors may be beneficial for patient survival. This short review highlights the potential benefits of glycolysis inhibition as well as controlling the elevated glucose levels in patients with the treatment of Covid-19.
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Affiliation(s)
- Fatma Ozlem Zurnaci
- Istanbul Medipol University, Research Institute for Health Sciences and Technologies (SABITA), Center of Drug Discovery and Development, Kavacik-Beykoz/Istanbul, 34810, Turkey.
- Istanbul Medipol University, Health Sciences Institute, Department of Molecular Medicine and Biotechnology, Kavacik Campus, Kavacik-Beykoz/ISTANBUL 34810, Turkey
| | - Mustafa Guzel
- Istanbul Medipol University, Research Institute for Health Sciences and Technologies (SABITA), Center of Drug Discovery and Development, Kavacik-Beykoz/Istanbul, 34810, Turkey.
- Istanbul Medipol University, Health Sciences Institute, Department of Molecular Medicine and Biotechnology, Kavacik Campus, Kavacik-Beykoz/ISTANBUL 34810, Turkey
- Istanbul Medipol University, International School of Medicine, Department of Medical Pharmacology, Kavacik Campus, Kavacik-Beykoz/ISTANBUL 34810, Turkey
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Cess CG, Finley SD. Multiscale modeling of tumor adaption and invasion following anti‐angiogenic therapy. COMPUTATIONAL AND SYSTEMS ONCOLOGY 2022. [DOI: 10.1002/cso2.1032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Affiliation(s)
- Colin G. Cess
- Department of Biomedical Engineering University of Southern California Los Angeles California USA
| | - Stacey D. Finley
- Department of Biomedical Engineering University of Southern California Los Angeles California USA
- Department of Quantitative and Computational Biology University of Southern California Los Angeles California USA
- Mork Family Department of Chemical Engineering and Materials Science University of Southern California Los Angeles California USA
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Chen Y, Li Y. Metabolic reprogramming and immunity in cancer. CANCER IMMUNOLOGY AND IMMUNOTHERAPY 2022:137-196. [DOI: 10.1016/b978-0-12-823397-9.00006-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Current Advancements of Plant-Derived Agents for Triple-Negative Breast Cancer Therapy through Deregulating Cancer Cell Functions and Reprogramming Tumor Microenvironment. Int J Mol Sci 2021; 22:ijms222413571. [PMID: 34948368 PMCID: PMC8703661 DOI: 10.3390/ijms222413571] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 12/12/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is defined based on the absence of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. Currently, chemotherapy is the major therapeutic approach for TNBC patients; however, poor prognosis after a standard chemotherapy regimen is still commonplace due to drug resistance. Abnormal tumor metabolism and infiltrated immune or stromal cells in the tumor microenvironment (TME) may orchestrate mammary tumor growth and metastasis or give rise to new subsets of cancer cells resistant to drug treatment. The immunosuppressive mechanisms established in the TME make cancer cell clones invulnerable to immune recognition and killing, and turn immune cells into tumor-supporting cells, hence allowing cancer growth and dissemination. Phytochemicals with the potential to change the tumor metabolism or reprogram the TME may provide opportunities to suppress cancer metastasis and/or overcome chemoresistance. Furthermore, phytochemical intervention that reprograms the TME away from favoring immunoevasion and instead towards immunosurveillance may prevent TNBC metastasis and help improve the efficacy of combination therapies as phyto-adjuvants to combat drug-resistant TNBC. In this review, we summarize current findings on selected bioactive plant-derived natural products in preclinical mouse models and/or clinical trials with focus on their immunomodulatory mechanisms in the TME and their roles in regulating tumor metabolism for TNBC prevention or therapy.
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Luby A, Alves-Guerra MC. Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy. Cancers (Basel) 2021; 13:5912. [PMID: 34885023 PMCID: PMC8656934 DOI: 10.3390/cancers13235912] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 12/18/2022] Open
Abstract
Over the past decade, advances in cancer immunotherapy through PD1-PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.
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Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells. Int J Mol Sci 2021; 22:ijms222212494. [PMID: 34830375 PMCID: PMC8621753 DOI: 10.3390/ijms222212494] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/06/2021] [Accepted: 11/17/2021] [Indexed: 12/18/2022] Open
Abstract
Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.
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Shin E, Koo JS. Glucose Metabolism and Glucose Transporters in Breast Cancer. Front Cell Dev Biol 2021; 9:728759. [PMID: 34552932 PMCID: PMC8450384 DOI: 10.3389/fcell.2021.728759] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.
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Affiliation(s)
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
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Zeng Z, Zhao Y, Chen Q, Zhu S, Niu Y, Ye Z, Hu P, Chen D, Xu P, Chen J, Hu C, Hu Y, Xu F, Tang J, Wang F, Han S, Huang M, Wang C, Zhao G. Hypoxic exosomal HIF-1α-stabilizing circZNF91 promotes chemoresistance of normoxic pancreatic cancer cells via enhancing glycolysis. Oncogene 2021; 40:5505-5517. [PMID: 34294845 DOI: 10.1038/s41388-021-01960-w] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 06/25/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
Research has indicated that hypoxia profoundly contributes to chemoresistance of pancreatic cancer (PC), while the precise mechanism has not been fully elucidated. In this study, we report a hypoxic exosomal circular RNA (circRNA)-mediated mechanism of conferred chemoresistance in PC cells. Gemcitabine (GEM) resistance was enhanced in normoxic PC cells incubated with exosomes derived from hypoxic PC cells. CircRNA microarray displayed that circZNF91 was remarkably increased in hypoxic exosomes of PC cells compared with normoxic exosomes. Overexpression of circZNF91 obviously stimulated chemoresistance in PC cells, while knockdown of circZNF91 retarded the hypoxic exosome-transmitted chemoresistance. Mechanistically, the hypoxic-induced exosomal circZNF91 transmitted into normoxic PC cells could competitively bind to miR-23b-3p, which deprives the inhibition of miR-23b-3p on expression of deacetylase Sirtuin1 (SIRT1). Consequently, the upregulated SIRT1 enhanced deacetylation-dependent stability of HIF-1α protein, leading to glycolysis and GEM chemoresistance of recipient PC cells. In addition, we revealed that the increased circZNF91 in hypoxic exosome was attributed to the transcriptional regulation by HIF-1α. Coincidently, transmission of hypoxic exosomes into subcutaneous xenografts in nude mice obviously facilitated the chemoresistance of transplanted PC tumor, which could be reversed by depletion of circZNF91 or upregulation of miR-23b-3p. Furthermore, clinical data showed that circZNF91 was significantly upregulated in PC tissues and correlated with overexpression of glycolytic enzymes and short overall survival time. Collectively, exosomal circZNF91 can function as a cargo mediating the signal transmission between hypoxic and normoxic tumor cells to promote GEM chemoresistance of PC and may potentially serve as a therapeutic target.
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Affiliation(s)
- Zhu Zeng
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Zhao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - QingYong Chen
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuai Zhu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Niu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zeng Ye
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Hu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ding Chen
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Xu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinghuang Chen
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chaojie Hu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuhang Hu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fengyu Xu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiang Tang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fan Wang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shengbo Han
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengqi Huang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunyou Wang
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Gang Zhao
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Wang J, Zhu W, Han J, Yang X, Zhou R, Lu H, Yu H, Yuan W, Li P, Tao J, Lu Q, Wei J, Yang H. The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. Cancer Commun (Lond) 2021; 41:560-575. [PMID: 33991457 PMCID: PMC8286140 DOI: 10.1002/cac2.12158] [Citation(s) in RCA: 155] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 01/16/2021] [Accepted: 04/09/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND As a rate-limiting enzyme of glycolysis, pyruvate kinase muscle isozyme M2 (PKM2) participates in tumor metabolism and growth. The regulatory network of PKM2 in cancer is complex and has not been fully studied in bladder cancer. The 5-methylcytidine (m5C) modification in PKM2 mRNA might participate in the pathogenesis of bladder cancer and need to be further clarified. This study aimed to investigate the biological function and regulatory mechanism of PKM2 in bladder cancer. METHODS The expression of PKM2 and Aly/REF export factor (ALYREF) was measured by Western blotting, qRT-PCR, and immunohistochemistry. The bioprocesses of bladder cancer cells were demonstrated by a series of experiments in vitro and in vivo. RNA immunoprecipitation, RNA-sequencing, and dual-luciferase reporter assays were conducted to explore the potential regulatory mechanisms of PKM2 in bladder cancer. RESULTS In bladder cancer, we first demonstrated that ALYREF stabilized PKM2 mRNA and bound to its m5C sites in 3'-untranslated regions. Overexpression of ALYREF promoted bladder cancer cell proliferation by PKM2-mediated glycolysis. Furthermore, high expression of PKM2 and ALYREF predicted poor survival in bladder cancer patients. Finally, we found that hypoxia-inducible factor-1alpha (HIF-1α) indirectly up-regulated the expression of PKM2 by activating ALYREF in addition to activating its transcription directly. CONCLUSIONS The m5C modification in PKM2 mRNA in the HIF-1α/ALYREF/PKM2 axis may promote the glucose metabolism of bladder cancer, providing a new promising therapeutic target for bladder cancer.
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Affiliation(s)
- Jing‐Zi Wang
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Wei Zhu
- Research Division of Clinical Pharmacologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Jie Han
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Xiao Yang
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Rui Zhou
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Hong‐Cheng Lu
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Hao Yu
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Wen‐Bo Yuan
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Peng‐Chao Li
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Jun Tao
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Qiang Lu
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Ji‐Fu Wei
- Research Division of Clinical Pharmacologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
| | - Haiwei Yang
- Department of Urologythe First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu210000P. R. China
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van Gisbergen MW, Zwilling E, Dubois LJ. Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio. Front Oncol 2021; 11:653621. [PMID: 34041023 PMCID: PMC8143268 DOI: 10.3389/fonc.2021.653621] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatment. These strategies, capable of either sensitizing or protecting tissues, target either tumor or normal tissue and are often focused on modulating of tissue oxygenation, hypoxia-inducible factor (HIF) stabilization, glucose metabolism, mitochondrial function and the redox balance. Several compounds or therapies are still in under (pre-)clinical development, while others are already used in clinical practice. Here, we describe different strategies from bench to bedside to optimize the therapeutic ratio through modulation of the cellular metabolism. This review gives an overview of the current state on development and the mechanism of action of modulators affecting cellular metabolism with the aim to improve the radiotherapy response on tumors or to protect the normal tissue and therefore contribute to an improved therapeutic ratio.
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Affiliation(s)
- Marike W van Gisbergen
- The M-Lab, Department of Precision Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.,Department of Dermatology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Emma Zwilling
- The M-Lab, Department of Precision Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Ludwig J Dubois
- The M-Lab, Department of Precision Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
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41
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Sebestyén A, Kopper L, Dankó T, Tímár J. Hypoxia Signaling in Cancer: From Basics to Clinical Practice. Pathol Oncol Res 2021; 27:1609802. [PMID: 34257622 PMCID: PMC8262153 DOI: 10.3389/pore.2021.1609802] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 12/24/2022]
Abstract
Cancer hypoxia, recognized as one of the most important hallmarks of cancer, affects gene expression, metabolism and ultimately tumor biology-related processes. Major causes of cancer hypoxia are deficient or inappropriate vascularization and systemic hypoxia of the patient (frequently induced by anemia), leading to a unique form of genetic reprogramming by hypoxia induced transcription factors (HIF). However, constitutive activation of oncogene-driven signaling pathways may also activate hypoxia signaling independently of oxygen supply. The consequences of HIF activation in tumors are the angiogenic phenotype, a novel metabolic profile and the immunosuppressive microenvironment. Cancer hypoxia and the induced adaptation mechanisms are two of the major causes of therapy resistance. Accordingly, it seems inevitable to combine various therapeutic modalities of cancer patients by existing anti-hypoxic agents such as anti-angiogenics, anti-anemia therapies or specific signaling pathway inhibitors. It is evident that there is an unmet need in cancer patients to develop targeted therapies of hypoxia to improve efficacies of various anti-cancer therapeutic modalities. The case has been opened recently due to the approval of the first-in-class HIF2α inhibitor.
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Affiliation(s)
- Anna Sebestyén
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - László Kopper
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Titanilla Dankó
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - József Tímár
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
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Arundhathi JRD, Mathur SR, Gogia A, Deo SVS, Mohapatra P, Prasad CP. Metabolic changes in triple negative breast cancer-focus on aerobic glycolysis. Mol Biol Rep 2021; 48:4733-4745. [PMID: 34047880 DOI: 10.1007/s11033-021-06414-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/16/2021] [Indexed: 02/06/2023]
Abstract
Among breast cancer subtypes, the triple negative breast cancer (TNBC) has the worst prognosis. In absence of any permitted targeted therapy, standard chemotherapy is the mainstay for TNBC treatment. Hence, there is a crucial need to identify potential druggable targets in TNBCs for its effective treatment. In recent times, metabolic reprogramming has emerged as cancer cells hallmark, wherein cancer cells display discrete metabolic phenotypes to fuel cell progression and metastasis. Altered glycolysis is one such phenotype, in which even in oxygen abundance majority of cancer cells harvest considerable amount of energy through elevated glycolytic-flux. In the present review, we attempt to summarize the role of key glycolytic enzymes i.e. HK, Hexokinase; PFK, Phosphofructokinase; PKM2, Pyruvate kinase isozyme type 2; and LDH, Lactate dehydrogenase in TNBCs, and possible therapeutic options presently available.
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Affiliation(s)
- J R Dev Arundhathi
- Department of Medical Oncology, Dr BRA IRCH, AIIMS, New Delhi, 110029, India
| | - Sandeep R Mathur
- Department of Pathology, Dr BRA IRCH, AIIMS, New Delhi, 110029, India
| | - Ajay Gogia
- Department of Medical Oncology, Dr BRA IRCH, AIIMS, New Delhi, 110029, India
| | - S V S Deo
- Department of Surgical Oncology, Dr BRA IRCH, AIIMS, New Delhi, 110029, India
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Zare ME, Kansestani AN, Hemmati S, Mansouri K, Vaisi-Raygani A. The rate of aerobic glycolysis is a pivotal regulator of tumor progression. J Diabetes Metab Disord 2021; 20:523-531. [PMID: 34178852 DOI: 10.1007/s40200-021-00774-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/18/2021] [Indexed: 12/30/2022]
Abstract
Purpose Cancer cells depend on glucose metabolism via exclusive glycolysis pathway is named Aerobic glycolysis or Warburg effect. The aim of this study was investigation of different glucose accessibility conditions on the rate of Warburg effect and its impact on Hypoxia inducible factors-1 α (HIF-1 α)/vascular endothelium growth factor (VEGF) pathway in breast cancer cells lines. Methods MDA-MB-231 (Warburg phenomenon) and MCF-7 (oxidative) cell lines were cultured in DMEM and exposed to three different glucose accessibility medium for 48 h (5.5 mM as normal glucose (NG), 25 mM as high glucose (HG) and 2-Deoxyglucose (2-DG) as restricted glucose accessibility). Glucose uptake, intra/extracellular lactate and pyruvate, HIF-1α accumulation and vascular endothelium growth factor (VEGF) expression were evaluated by standard methods. Results Our results showed in NG condition both of cell lines produce lactate, but it was higher in MDA-MB-231. HG condition increased extracellular lactate in both cell lines especially in MCF-7 cells whereas intracellular lactate and pyruvate raised only in MCF-7. 2-DG decreased extracellular and intracellular lactate and pyruvate in both cell lines especially in MDA-MB-231. HIF-1α accumulation was detectable in NG condition in both cell lines. HG condition increased HIF-1α accumulation in MCF-7 cells but not in MDA-MB-231 and 2-DG decreased it in both call lines, especially in MDA-MB-231. Expression of VEGF had similar pattern with HIF-1α in different conditions. Conclusions Our findings revealed the rate of Warburg effect is an important indicator for tumor promotion and invasion due to its impacts on important transcription factors like HIF-1α.
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Affiliation(s)
- Mohammad Erfan Zare
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Clinical Biochemistry, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Atefeh Nasir Kansestani
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shahrooz Hemmati
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Asad Vaisi-Raygani
- Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Daneshgah Avenue, Kermanshah, 67148-69914 Iran
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Jiang J, Roman J, Xu HN, Li LZ. An Observation on Enhanced Extracellular Acidification and Lactate Production Induced by Inhibition of Lactate Dehydrogenase A. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1269:163-167. [PMID: 33966212 PMCID: PMC8189668 DOI: 10.1007/978-3-030-48238-1_26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The Warburg effect, representing enhanced glycolysis and lactate production in adequately oxygenated cancer cells, has been widely regarded to cause increased extracellular acidification. Converting pyruvate to lactate by lactate dehydrogenase A (LDHA) is the last step of glycolysis. Here, we report an interesting counterintuitive observation that inhibition of LDHA resulted in enhanced glycolysis in MDA-MB-231 breast cancer cells. The cells were treated with FX11 (7-benzyl-2,3-dihydroxy-6-methyl-4-propylnaphthalene-1-carboxylic acid), a specific LDHA inhibitor. Seahorse assay reported dose-dependent increases in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Independent biochemical measurements also confirmed the increase of lactate production under FX11 treatment. The reasons and mechanism of these observations of elevated ECAR and lactate production in the MDA-MB-231 breast cancer cells under FX11 treatment remain to be investigated.
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Affiliation(s)
- Jinxia Jiang
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jeffrey Roman
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - He N Xu
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Lin Z Li
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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45
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Han S, Oh JS, Kim JS. Immune microenvironment of the gene signature reflecting the standardised uptake value on 18F-fluorodeoxyglucose positron emission tomography/computed tomography in head and neck squamous cell carcinoma. Ann Nucl Med 2021; 35:65-75. [PMID: 33044632 DOI: 10.1007/s12149-020-01537-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/30/2020] [Indexed: 01/15/2023]
Abstract
OBJECTIVE A comprehensive understanding of the link between 18F-FDG PET/CT and the tumor immune microenvironment (TIM) is lacking. We, therefore, investigated the TIM in regard to the gene signature of 18F-FDG PET/CT in head and neck squamous cell carcinoma (HNSC). METHODS The mRNA sequence data of 480 HNSC patients on The Cancer Genome Atlas portal were used to explore genes showing high associations with maximum standardised uptake value (SUVmax) on 18F-FDG PET/CT based on Pearson correlation test. Hierarchical clustering of the selected gene signature was performed and divided patients into high and low SUV clusters. Principal component analysis was performed to derive the summarised expression profile of the gene signature and defined the first principal component scores as the SUV signature scores (SUVSSs). The SUV clusters and SUVSS based on the gene signature were characterised by overall survival, clinical variables, and the immune microenvironment in terms of overall immune score, immune cell type enrichment score, expression of immunomodulator genes as well as somatic copy number alterations (SCNA) possibly contributing to immune cell recognition. RESULTS The high SUV cluster classified by the gene signature (191 genes) was an independent predictor of overall survival (adjusted hazard ratio 1.40, p = 0.022). The SUVSS values differed across the molecular subtypes of HNSC (p < 0.001), and HPV status (p = 0.024). Tumors in the low SUV cluster exhibited significantly higher overall immune score and lower SCNA scores (p < 0.05 for all) compared with tumors in the high SUV cluster. The low SUV cluster showed an immune cell composition consisting of high levels of T cells, B cells, mast cells, neutrophils, monocytes, and eosinophils, but lower basophils and similar macrophage levels to the high SUV cluster. Differential gene expression analysis demonstrated SUV cluster-distinct expression of several immunomodulators including PD-1, CD40LG, IL2RA, TLR4, BTLA, and TIGIT. CONCLUSION HNSC exhibited the distinct TIM according to the gene signature reflecting SUVmax on 18F-FDG PET/CT. Our results support an understanding of the close relationship between FDG uptake and tumor immune response, and suggest that 18F-FDG PET/CT could be clinically usable as a biomarker for assisting immunotherapy.
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Affiliation(s)
- Sangwon Han
- Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Jungsu S Oh
- Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea
| | - Jae Seung Kim
- Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.
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46
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Wang X, Jiang Z, Yang H, Zhang Y, Xu L. Hypoxia-induced FOXO4/LDHA axis modulates gastric cancer cell glycolysis and progression. Clin Transl Med 2021; 11:e279. [PMID: 33463054 PMCID: PMC7809603 DOI: 10.1002/ctm2.279] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND AND AIM We previously identified forkhead box (FOX) O4 mRNA as a predictor in gastric cancer (GC). However, the underlying mechanism has yet to be elucidated. We aimed to illustrate the mechanism by which FOXO4 regulated glycolysis under hypoxia in GC. METHODS FOXO4 protein expression was investigated by immunohistochemical staining of 252 GC and their normal adjacent tissues. We restored or silenced FOXO4 expression in GC cell lines to explore the underlying mechanisms. RESULTS FOXO4 was downregulated in GC. Loss of FOXO4 expression was validated in univariate and multivariate survival analysis as an independent prognostic predictor for overall survival (P < 0.05) and disease-free survival (P<0.05). Restored FOXO4 expression significantly impaired the glycolysis rate in GC cells, while silencing FOXO4 expression enhanced glycolysis rate. FOXO4 expression was inversely associated with maximum standardized uptake value in mice models and patient samples. Mechanistically, FOXO4 bound to the glycolytic enzyme lactate dehydrogenase (LDH)A promoter and inactivated its activity in a dose-dependent manner (P < 0.05). Finally, we determined that FOXO4 was a transcriptional target of hypoxia-inducible factor (HIF) -1α, which is central in response to hypoxia. CONCLUSIONS Our data suggested that FOXO4 plays a key role in the regulation of glycolysis in GC, and disrupting the HIF-1α-FOXO4-LDHA axis might be a promising therapeutic strategy for GC.
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Affiliation(s)
- Xiao‐Hong Wang
- Department of GastroenterologyThe Second Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Zhong‐Hua Jiang
- Department of GastroenterologyThe Yancheng Clinical College of Xuzhou Medical UniversityYanchengJiangsuChina
- Department of GastroenterologyThe First People's Hospital of YanchengYanchengJiangsuChina
| | - Hong‐Mei Yang
- Department of GastroenterologyThe Yancheng Clinical College of Xuzhou Medical UniversityYanchengJiangsuChina
- Department of GastroenterologyThe First People's Hospital of YanchengYanchengJiangsuChina
| | - Yu Zhang
- Department of GastroenterologyThe Second Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | - Li‐Hua Xu
- Department of GastroenterologyThe Sixth People's Hospital of NantongNantongJiangsuChina
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Wood EG, Macdougall CE, Blythe H, Clément M, Colas RA, Dalli J, Marelli-Berg F, Longhi MP. HIF1α activation in dendritic cells under sterile conditions promotes an anti-inflammatory phenotype through accumulation of intracellular lipids. Sci Rep 2020; 10:20825. [PMID: 33257753 PMCID: PMC7705732 DOI: 10.1038/s41598-020-77793-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 11/11/2020] [Indexed: 02/08/2023] Open
Abstract
Obesity is among the leading causes of elevated cardiovascular disease mortality and morbidity. Adipose tissue dysfunction, insulin resistance and inflammation are recognized as important risk factors for the development of cardiovascular disorders in obesity. Hypoxia appears to be a key factor in adipose tissue dysfunction affecting not only adipocytes but also immune cell function. Here we examined the effect of hypoxia-induced transcription factor HIF1α activation on classical dendritic cell (cDCs) function during obesity. We found that deletion of Hif1α on cDCs results in enhanced adipose-tissue inflammation and atherosclerotic plaque formation in a mouse model of obesity. This effect is mediated by HIF1α-mediated increased lipid synthesis, accumulation of lipid droplets and alter synthesis of lipid mediators. Our findings demonstrate that HIF1α activation in cDCs is necessary to control vessel wall inflammation.
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Affiliation(s)
- Elizabeth G Wood
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Claire E Macdougall
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Hazel Blythe
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Marc Clément
- INSERM U1148, Laboratory for Vascular Translational Science, Hôpital Bichat, 46 rue Henri Huchard, 75018, Paris Cedex, France
| | - Romain A Colas
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Jesmond Dalli
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Federica Marelli-Berg
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK
| | - M Paula Longhi
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
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Cancer Stem Cell-Associated Pathways in the Metabolic Reprogramming of Breast Cancer. Int J Mol Sci 2020; 21:ijms21239125. [PMID: 33266219 PMCID: PMC7730588 DOI: 10.3390/ijms21239125] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 02/07/2023] Open
Abstract
Metabolic reprogramming of cancer is now considered a hallmark of many malignant tumors, including breast cancer, which remains the most commonly diagnosed cancer in women all over the world. One of the main challenges for the effective treatment of breast cancer emanates from the existence of a subpopulation of tumor-initiating cells, known as cancer stem cells (CSCs). Over the years, several pathways involved in the regulation of CSCs have been identified and characterized. Recent research has also shown that CSCs are capable of adopting a metabolic flexibility to survive under various stressors, contributing to chemo-resistance, metastasis, and disease relapse. This review summarizes the links between the metabolic adaptations of breast cancer cells and CSC-associated pathways. Identification of the drivers capable of the metabolic rewiring in breast cancer cells and CSCs and the signaling pathways contributing to metabolic flexibility may lead to the development of effective therapeutic strategies. This review also covers the role of these metabolic adaptation in conferring drug resistance and metastasis in breast CSCs.
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Targeting lactate production and efflux in prostate cancer. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165894. [PMID: 32650130 DOI: 10.1016/j.bbadis.2020.165894] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/24/2022]
Abstract
Prostate cancer (PCa) is the most commonly diagnosed cancer in men worldwide. Screening and management of PCa remain controversial and, therefore, the discovery of novel molecular biomarkers is urgently needed. Alteration in cancer cell metabolism is a recognized hallmark of cancer, whereby cancer cells exhibit high glycolytic rates with subsequent lactate production, regardless of oxygen availability. To maintain the hyperglycolytic phenotype, cancer cells efficiently export lactate through the monocarboxylate transporters MCT1 and MCT4. The impact of inhibiting lactate production/extrusion on PCa cell survival and aggressiveness was investigated in vitro and ex vivo using primary tumor and metastatic PCa cell lines and the chicken embryo chorioallantoic membrane (CAM) model. In this study, we showed the metastatic PCa cell line (DU125) displayed higher expression levels of MCT1/4 isoforms and glycolysis-related markers than the localized prostate tumor-derived cell line (22RV1), indicating these proteins are differentially expressed throughout prostate malignant transformation. Moreover, disruption of lactate export by MCT1/4 silencing resulted in a decrease in PCa cell growth and motility. To support these results, we pharmacological inhibited lactate production (via inhibition of LDH) and release (via inhibition of MCTs) and a reduction in cancer cell growth in vitro and in vivo was observed. In summary, our data provide evidence that MCT1 and MCT4 are important players in prostate neoplastic progression and that inhibition of lactate production/export can be explored as a strategy for PCa treatment.
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Zhou R, Li S, Mei X, Jiang T, Wang Q. Remifentanil up-regulates HIF1α expression to ameliorate hepatic ischaemia/reperfusion injury via the ZEB1/LIF axis. J Cell Mol Med 2020; 24:13196-13207. [PMID: 32996684 PMCID: PMC7701522 DOI: 10.1111/jcmm.15929] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/11/2020] [Accepted: 09/08/2020] [Indexed: 12/20/2022] Open
Abstract
Ischaemia/reperfusion (I/R)-induced hepatic injury is regarded as a main reason of hepatic failure after transplantation or lobectomy. The current study aimed to investigate how the opioid analgesic remifentanil treatment affects I/R-induced hepatic injury and explore the possible mechanisms related to HIF1α. Initially, an I/R-induced hepatic injury animal model was established in C57BL/6 mice, and an in vitro hypoxia-reoxygenation model was constructed in NCTC-1469 cells, followed by remifentanil treatment and HIF1α silencing treatment. The levels of blood glucose, lipids, alanine transaminase (ALT) and aspartate transaminase (AST) in mouse serum were measured using automatic chemistry analyser, while the viability and apoptosis of cells were detected using CCK8 assay and flow cytometry. Our results revealed that mice with I/R-induced hepatic injury showed higher serum levels of blood glucose, lipids, ALT and AST and leukaemia inhibitory factor (LIF) expression, and lower HIF1α and ZEB1 expression (P < .05), which were reversed after remifentanil treatment (P < .05). Besides, HIF1α silencing increased the serum levels of blood glucose, lipids, ALT and AST (P < .05). Furthermore, hypoxia-induced NCTC-1469 cells exhibited decreased HIF1α and ZEB1 expression, reduced cell viability, as well as increased LIF expression and cell apoptosis (P < .05), which were reversed by remifentanil treatment (P < .05). Moreover, HIF1α silencing down-regulated ZEB1 expression, decreased cell viability, and increased cell apoptosis (P < .05). ZEB1 was identified to bind to the promoter region of LIF and inhibit its expression. In summary, remifentanil protects against hepatic I/R injury through HIF1α and downstream effectors.
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Affiliation(s)
- Rongsheng Zhou
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuang Li
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaopeng Mei
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Tao Jiang
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qiang Wang
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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