Androgen-Dependent Prostate Cancer Cells Reprogram Their Metabolic Signature upon GLUT1 Upregulation by Manganese Superoxide Dismutase
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. Enzymatic Activity
2.3. H2O2 Quantification
2.4. Western Blot
2.5. Measure of Metabolic Flux Profile
2.6. Glucose-Uptake Assay
2.7. Pentose Phosphate Assay
2.8. Animal Experimental Procedures
2.9. Metabolomic Assay
2.10. Mitotracker Staining
2.11. Flow Cytometry: Cell-Cycle Analysis and Annexin V Staining
2.12. MTT
2.13. Human Prostate Samples
2.14. Immunohistochemistry and Immunocytochemistry
2.15. Statistical Analysis
3. Results
3.1. Stable SOD2 Overexpression Increases GLUT-1 Levels and Glucose Uptake, Altering Glycolysis and OXPHOS
3.2. SOD2 Increases Glucose Uptake in Mice
3.3. Prostate Adenocarcinoma Cells Overexpressing SOD2 Present a Metabolic Rearrangement of Krebs Cycle and Aminoacidic Pathways
3.4. Survival to Glucose Deprivation Is Ameliorated by SOD2 Overexpression
3.5. GLUT-1 and SOD2 Levels Correlate Spatially in Human Prostate Cancer
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- UICC. Globocan WHO: Europe Fact-Sheets 2018; UICC: Geneva, Switzerland, 2018. [Google Scholar]
- Wei, L.; Wang, J.; Lampert, E.; Schlanger, S.; DePriest, A.D.; Hu, Q.; Gomez, E.C.; Murakam, M.; Glenn, S.T.; Conroy, J.; et al. Intratumoral and Intertumoral Genomic Heterogeneity of Multifocal Localized Prostate Cancer Impacts Molecular Classifications and Genomic Prognosticators. Eur. Urol. 2016, 71, 183–192. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Costello, L.C.; Franklin, R.B. The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: Connecting the dots. Mol. Cancer 2006, 5, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gonzalez-Menendez, P.; Hevia, D.; Mayo, J.C.; Sainz, R.M. The dark side of glucose transporters in prostate cancer: Are they a new feature to characterize carcinomas? Int. J. Cancer 2017, 142, 2414–2424. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kasper, J.S.; Liu, Y.; Giovannucci, E. Diabetes mellitus and risk of prostate cancer in the health professionals follow-up study. Int. J. Cancer 2008, 124, 1398–1403. [Google Scholar] [CrossRef] [Green Version]
- Lebovitz, R.M.; Zhang, H.; Vogel, H.; Cartwright, J., Jr.; Dionne, L.; Lu, N.; Huang, S.; Matzuk, M.M. Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc. Natl. Acad. Sci. USA 1996, 93, 9782–9787. [Google Scholar] [CrossRef] [Green Version]
- Li, Y.; Huang, T.-T.; Carlson, E.J.; Melov, S.; Ursell, P.C.; Olson, J.L.; Noble, L.J.; Yoshimura, M.P.; Berger, C.; Chan, P.H.; et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat. Genet. 1995, 11, 376–381. [Google Scholar] [CrossRef]
- Mayo, J.; Sainz, R.; Quirós-Gonzalez, I. MnSOD/SOD2 in Cancer: The Story of a Double Agent. React. Oxyg. Species 2018, 5, 86–106. [Google Scholar] [CrossRef]
- Quiros-Gonzalez, I.; Sainz, R.M.; Hevia, D.; Mayo, J.C. MnSOD drives neuroendocrine differentiation, androgen independence, and cell survival in prostate cancer cells. Free Radic. Biol. Med. 2011, 50, 525–536. [Google Scholar] [CrossRef]
- Quirós, I.; Sáinz, R.M.; Hevia, D.; García-Suárez, O.; Astudillo, A.; Rivas, M.; Mayo, J.C. Upregulation of manganese superoxide dismutase (SOD2) is a common pathway for neuroendocrine differentiation in prostate cancer cells. Int. J. Cancer 2009, 125, 1497–1504. [Google Scholar] [CrossRef]
- Kucukgergin, C.; Sanli, O.; Tefik, T.; Aydın, M.; Ozcan, F.; Seckin, S. Increased risk of advanced prostate cancer associated with MnSOD Ala-9-Val gene polymorphism. Mol. Biol. Rep. 2011, 39, 193–198. [Google Scholar] [CrossRef]
- Miar, A.; Hevia, D.; Muñoz-Cimadevilla, H.; Astudillo, A.; Velasco, J.; Sainz, R.M.; Mayo, J.C. Manganese superoxide dismutase (SOD2/MnSOD)/catalase and SOD2/GPx1 ratios as biomarkers for tumor progression and metastasis in prostate, colon, and lung cancer. Free Radic. Biol. Med. 2015, 85, 45–55. [Google Scholar] [CrossRef] [PubMed]
- Al Haq, A.T.; Tseng, H.-Y.; Chen, L.-M.; Wang, C.-C.; Hsu, H.-L. Targeting prooxidant MnSOD effect inhibits triple-negative breast cancer (TNBC) progression and M2 macrophage functions under the oncogenic stress. Cell Death Dis. 2022, 13, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Sciarra, A.; Maggi, M.; Salciccia, S.; Nicolai, A.; Tortorella, E.; Giantulli, S.; Magliocca, F.M.; Silvestri, I.; Taglieri, L.; Cattarino, S.; et al. Tissue Expression of Androgen Receptor Splice Variant 7 at Radical Prostatectomy Predicts Risk of Progression in Untreated Nonmetastatic Prostate Cancer. Oncology 2021, 99, 251–255. [Google Scholar] [CrossRef]
- Gonzalez-Meneéndez, R.; Hevia, D.; Rodriguez-Garcia, A.; Mayo, J.C.; Sainz, R.M. Regulation of GLUT Transporters by Flavonoids in Androgen-Sensitive and -Insensitive Prostate Cancer Cells. Endocrinology 2014, 155, 3238–3250. [Google Scholar] [CrossRef] [Green Version]
- Shiota, M.; Yokomizo, A.; Naito, S. Oxidative stress and androgen receptor signaling in the development and progression of castration-resistant prostate cancer. Free Radic. Biol. Med. 2011, 51, 1320–1328. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Lu, P.; Zhou, S.; Zhang, L.; Zhao, J.-H.; Tang, J.-H. Predictive value of glucose transporter-1 and glucose transporter-3 for survival of cancer patients: A meta-analysis. Oncotarget 2017, 8, 13206–13213. [Google Scholar] [CrossRef]
- Stewart, G.D.; Gray, K.; Pennington, C.J.; Edwards, D.R.; Riddick, A.C.; Ross, J.A.; Habib, F.K. Analysis of hypoxia-associated gene expression in prostate cancer: Lysyl oxidase and glucose transporter-1 expression correlate with Gleason score. Oncol. Rep. 1994, 20, 1561–1567. [Google Scholar] [CrossRef] [Green Version]
- Ho, Y.-S.; Vincent, R.; Dey, M.S.; Slot, J.W.; Crapo, J.D. Transgenic Models for the Study of Lung Antioxidant Defense: Enhanced Manganese-containing Superoxide Dismutase Activity Gives Partial Protection to B6C3 Hybrid Mice Exposed to Hyperoxia. Am. J. Respir. Cell Mol. Biol. 1998, 18, 538–547. [Google Scholar] [CrossRef] [Green Version]
- Zhao, S.; Guo, Y.; Sheng, Q.; Shyr, Y. Advanced Heat Map and Clustering Analysis Using Heatmap3. BioMed Res. Int. 2014, 2014, 986048. [Google Scholar] [CrossRef] [Green Version]
- Chong, J.; Wishart, D.S.; Xia, J. Using MetaboAnalyst 4.0 for Comprehensive and Integrative Metabolomics Data Analysis. Curr. Protoc. Bioinform. 2019, 68, e86. [Google Scholar] [CrossRef]
- Gonzalez-Menendez, P.; Hevia, D.; Alonso-Arias, R.; Álvarez-Artime, A.; Rodriguez-Garcia, A.; Kinet, S.; Gonzalez-Pola, I.; Taylor, N.; Mayo, J.C.; Sainz, R.M. GLUT1 protects prostate cancer cells from glucose deprivation-induced oxidative stress. Redox Biol. 2018, 17, 112–127. [Google Scholar] [CrossRef]
- Hart, P.; Mao, M.; De Abreu, A.L.P.; Ansenberger-Fricano, K.; Ekoue, D.N.; Ganini, D.; Kajdacsy-Balla, A.; Diamond, A.M.; Minshall, R.D.; Consolaro, M.E.L.; et al. MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nat. Commun. 2015, 6, 1–14. [Google Scholar] [CrossRef] [Green Version]
- Plecitá-Hlavatá, L.; Engstová, H.; Holendová, B.; Tauber, J.; Špaček, T.; Petrásková, L.; Křen, V.; Špačková, J.; Gotvaldová, K.; Ježek, J.; et al. Mitochondrial Superoxide Production Decreases on Glucose-Stimulated Insulin Secretion in Pancreatic β Cells Due to Decreasing Mitochondrial Matrix NADH/NAD+Ratio. Antioxid. Redox Signal. 2020, 33, 789–815. [Google Scholar] [CrossRef] [PubMed]
- Zhou, C.; Lyu, L.; Miao, H.; Bahr, T.; Zhang, Q.; Liang, T.; Zhou, H.; Chen, G.; Bai, Y. Redox regulation by SOD2 modulates colorectal cancer tumorigenesis through AMPK-mediated energy metabolism. Mol. Carcinog. 2020, 59, 545–556. [Google Scholar] [CrossRef] [PubMed]
- Bader, D.A.; Hartig, S.M.; Putluri, V.; Foley, C.; Hamilton, M.P.; Smith, E.A.; Saha, P.K.; Panigrahi, A.; Walker, C.; Zong, L.; et al. Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer. Nat. Metab. 2018, 1, 70–85. [Google Scholar] [CrossRef] [PubMed]
- Tomaszewski, M.; Quiros-Gonzalez, I.; O’Connor, J.P.; Abeyakoon, O.; Parker, G.; Williams, K.J.; Gilbert, F.; Bohndiek, S.E. Oxygen Enhanced Optoacoustic Tomography (OE-OT) Reveals Vascular Dynamics in Murine Models of Prostate Cancer. Theranostics 2017, 7, 2900–2913. [Google Scholar] [CrossRef] [PubMed]
- Faubert, B.; Vincent, E.; Griss, T.; Samborska, B.; Izreig, S.; Svensson, R.U.; Mamer, O.A.; Avizonis, D.; Shackelford, D.B.; Shaw, R.J.; et al. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1. Proc. Natl. Acad. Sci. USA 2014, 111, 2554–2559. [Google Scholar] [CrossRef] [Green Version]
- KEGG Enzyme 2.6.1.2 Alanine Transaminase. Available online: https://www.genome.jp/dbget-bin/www_bget?ec:2.6.1.2 (accessed on 10 December 2021).
- Nietzel, T.; Mostertz, J.; Ruberti, C.; Née, G.; Fuchs, P.; Wagner, S.; Moseler, A.; Müeller, S.J.; Benamar, A.; Poschet, G.; et al. Redox-mediated kick-start of mitochondrial energy metabolism drives resource-efficient seed germination. Proc. Natl. Acad. Sci. USA 2020, 117, 741–751. [Google Scholar] [CrossRef]
- Pozza, E.D.; Dando, I.; Pacchiana, R.; Liboi, E.; Scupoli, M.T.; Donadelli, M.; Palmieri, M. Regulation of succinate dehydrogenase and role of succinate in cancer. Semin. Cell Dev. Biol. 2020, 98, 4–14. [Google Scholar] [CrossRef] [PubMed]
- Tessem, M.-B.; Bertilsson, H.; Angelsen, A.; Bathen, T.F.; Drabløs, F.; Rye, M.B. A Balanced Tissue Composition Reveals New Metabolic and Gene Expression Markers in Prostate Cancer. PLoS ONE 2016, 11, e0153727. [Google Scholar] [CrossRef]
- Sutton, A.; Khoury, H.; Prip-Buus, C.; Cepanec, C.; Pessayre, D.; Degoul, F. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenetics 2003, 13, 145–157. [Google Scholar] [CrossRef] [PubMed]
- Sutton, A.; Imbert, A.; Igoudjil, A.; Descatoire, V.; Cazanave, S.; Pessayre, D.; Degoul, F. The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability. Pharm. Genom. 2005, 15, 311–319. [Google Scholar] [CrossRef] [PubMed]
- Ergen, A.; Narter, F.; Timirci, O.; Isbir, T. Effects of manganase superoxide dismutase Ala-9Val polymorphism on prostate cancer: A case-control study. Anticancer Res. 2007, 27, 1227–1230. [Google Scholar]
- Mikhak, B.; Hunter, D.J.; Spiegelman, D.; Platz, E.A.; Wu, K.; Erdman, J.W.; Giovannucci, E. Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid levels and prostate cancer risk. Carcinogenesis 2008, 29, 2335–2340. [Google Scholar] [CrossRef] [Green Version]
- Kang, D.; Lee, K.-M.; Park, S.K.; Berndt, S.I.; Peters, U.; Reding, D.; Chatterjee, N.; Welch, R.; Chanock, S.; Huang, W.-Y.; et al. Functional Variant of Manganese Superoxide Dismutase (SOD2 V16A) Polymorphism Is Associated with Prostate Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Study. Cancer Epidemiol. Biomark. Prev. 2007, 16, 1581–1586. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sies, H.; Jones, D.P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 2020, 21, 363–383. [Google Scholar] [CrossRef]
- Crocetto, F.; di Zazzo, E.; Buonerba, C.; Aveta, A.; Pandolfo, S.D.; Barone, B.; Trama, F.; Caputo, V.F.; Scafuri, L.; Ferro, M.; et al. Kaempferol, Myricetin and Fisetin in Prostate and Bladder Cancer: A Systematic Review of the Literature. Nutrients 2021, 13, 3750. [Google Scholar] [CrossRef]
- Nakanishi, S.; Yamane, K.; Ohishi, W.; Nakashima, R.; Yoneda, M.; Nojima, H.; Watanabe, H.; Kohno, N. Manganese superoxide dismutase Ala16Val polymorphism is associated with the development of type 2 diabetes in Japanese-Americans. Diabetes Res. Clin. Pr. 2008, 81, 381–385. [Google Scholar] [CrossRef]
- Flekac, M.; Skrha, J.; Hilgertova, J.; Lacinova, Z.; Jarolimkova, M. Gene polymorphisms of superoxide dismutases and catalase in diabetes mellitus. BMC Med. Genet. 2008, 9, 30. [Google Scholar] [CrossRef] [Green Version]
- Mena, E.; Lindenberg, L.M.; Choyke, P.L. New Targets for PET Molecular Imaging of Prostate Cancer. Semin. Nucl. Med. 2019, 49, 326–336. [Google Scholar] [CrossRef]
- De Visschere, P.J.; Standaert, C.; Fütterer, J.J.; Villeirs, G.M.; Panebianco, V.; Walz, J.; Maurer, T.; Hadaschik, B.A.; Lecouvet, F.E.; Giannarini, G.; et al. A Systematic Review on the Role of Imaging in Early Recurrent Prostate Cancer. Eur. Urol. Oncol. 2019, 2, 47–76. [Google Scholar] [CrossRef] [PubMed]
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Quiros-Gonzalez, I.; Gonzalez-Menendez, P.; Mayo, J.C.; Hevia, D.; Artime-Naveda, F.; Fernandez-Vega, S.; Fernandez-Fernandez, M.; Rodriguez-Gonzalez, P.; Garcia-Alonso, J.I.; Sainz, R.M. Androgen-Dependent Prostate Cancer Cells Reprogram Their Metabolic Signature upon GLUT1 Upregulation by Manganese Superoxide Dismutase. Antioxidants 2022, 11, 313. https://doi.org/10.3390/antiox11020313
Quiros-Gonzalez I, Gonzalez-Menendez P, Mayo JC, Hevia D, Artime-Naveda F, Fernandez-Vega S, Fernandez-Fernandez M, Rodriguez-Gonzalez P, Garcia-Alonso JI, Sainz RM. Androgen-Dependent Prostate Cancer Cells Reprogram Their Metabolic Signature upon GLUT1 Upregulation by Manganese Superoxide Dismutase. Antioxidants. 2022; 11(2):313. https://doi.org/10.3390/antiox11020313
Chicago/Turabian StyleQuiros-Gonzalez, Isabel, Pedro Gonzalez-Menendez, Juan C. Mayo, David Hevia, Francisco Artime-Naveda, Sheila Fernandez-Vega, Mario Fernandez-Fernandez, Pablo Rodriguez-Gonzalez, José I. Garcia-Alonso, and Rosa M. Sainz. 2022. "Androgen-Dependent Prostate Cancer Cells Reprogram Their Metabolic Signature upon GLUT1 Upregulation by Manganese Superoxide Dismutase" Antioxidants 11, no. 2: 313. https://doi.org/10.3390/antiox11020313
APA StyleQuiros-Gonzalez, I., Gonzalez-Menendez, P., Mayo, J. C., Hevia, D., Artime-Naveda, F., Fernandez-Vega, S., Fernandez-Fernandez, M., Rodriguez-Gonzalez, P., Garcia-Alonso, J. I., & Sainz, R. M. (2022). Androgen-Dependent Prostate Cancer Cells Reprogram Their Metabolic Signature upon GLUT1 Upregulation by Manganese Superoxide Dismutase. Antioxidants, 11(2), 313. https://doi.org/10.3390/antiox11020313