The role of redox homeostasis biomarkers in clear cell renal cell carcinoma development and progression
Abstract
The clear cell renal cell carcinoma (ccRCC) is the most frequent and the most aggresive subtype of renal cell carcinoma usually detected at an already advanced stage. It might even be observed as a metabolic disease since complex molecular changes and disturbed redox homeostasis are its hallmark. As certain changes are characteristic for tumorigenesis while some other for metastatic disease, the identification of metabolic modifications could also point out the stage of tumor progression. Hypoxia inducible factor, as a factor regulating transcription of genes encoding glycolytic enzymes, as well as controlling lipid accumulation, has a particular place in ccRCC development. Additionaly, disturbed redox homeostasis induces the Keap1/Nrf2 pathway which further modulates the synthesis of phase-II detoxifying metabolism enzymes. The upregulation of glutathione transferases, Pi class especially, inhibits kinase-dependent apoptosis that is essential in tumor progression. Furthermore, hydrogen peroxide (H2O2) acts as a signaling molecule conveying redox signals, while superoxide dismutase, as well as glutathione peroxidase are enzymes involved in its production and degradation. Hence, the activity of these enzymes impacts hydrogen peroxide levels and consequentially the ability of ccRCC cells to evade negative effect of reactive oxygen species.
References
[1] Hanahan, D.; Weinberg, R.A. The Hallmarks of Cancer. Cell, 2000, 100, 57–70.
[2] Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The next Generation. Cell, 2011, 144, 646–674.
[3] De Berardinis, R.J.; Chandel, N.S. Fundamentals of Cancer Metabolism. Sci. Adv., 2016, 2.
[4] Ljungberg, B.; Albiges, L.; Abu-Ghanem, Y.; Bensalah, K.; Dabestani, S.; Montes, S.F.P.; Giles, R.H.; Hofmann, F.; Hora, M.; Kuczyk, M.A.; Kuusk, T.; Lam, T.B.; Marconi, L.; Merseburger, A.S.; Powles, T.; Staehler, M.; Tahbaz, R.; Volpe, A.; Bex, A. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. Eur. Urol., 2019, 75, 799–810.
[5] Protzel, C.; Maruschke, M.; Hakenberg, O.W. Epidemiology, Aetiology, and Pathogenesis of Renal Cell Carcinoma. Eur. Urol. Suppl., 2012, 11, 52–59.
[6] Warren, A.Y.; Harrison, D. WHO/ISUP Classification, Grading and Pathological Staging of Renal Cell Carcinoma: Standards and Controversies. World J. Urol., 2018, 36, 1913–1926.
[7] Qiu, B.; Ackerman, D.; Sanchez, D.J.; Li, B.; Ochocki, J.D.; Grazioli, A.; Bobrovnikova-Marjon, E.; Alan Diehl, J.; Keith, B.; Celeste Simon, M. HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma. Cancer Discov., 2016, 5, 653–667.
[8] Wettersten, H.I.; Hakimi, A.A.; Morin, D.; Bianchi, C.; Johnstone, M.E.; Donohoe, D.R.; Trott, J.F.; Abu Aboud, O.; Stirdivant, S.; Neri, B.; Wolfert, R.; Stewart, B.; Perego, R.; Hsieh, J.J.; Weiss, R.H. Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis. Cancer Res, 2015, 75, 2541–2552.
[9] Chen, F.; Zhang, Y.; Şenbabaoğlu, Y.; Ciriello, G.; Yang, L.; Reznik, E.; Shuch, B.; Micevic, G.; De Velasco, G.; Shinbrot, E.; Noble, M.S.; Lu, Y.; Covington, K.R.; Xi, L.; Drummond, J.A.; Muzny, D.; Kang, H.; Lee, J.; Tamboli, P.; Reuter, V.; Shelley, C.S.; Kaipparettu, B.A.; Bottaro, D.P.; Godwin, A.K.; Gibbs, R.A.; Getz, G.; Kucherlapati, R.; Park, P.J.; Sander, C.; Henske, E.P.; Zhou, J.H.; Kwiatkowski, D.J.; Ho, T.H.; Choueiri, T.K.; Hsieh, J.J.; Akbani, R.; Mills, G.B.; Hakimi, A.A.; Wheeler, D.A.; Creighton, C.J. Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma. Cell Rep., 2016, 14, 2476–2489.
[10] Pandey, N.; Lanke, V.; Vinod, P.K. Network-Based Metabolic Characterization of Renal Cell Carcinoma. Sci. Rep., 2020, 10, 5955.
[11] Gordan, J.D.; Lal, P.; Dondeti, V.R.; Letrero, R.; Parekh, K.N.; Oquendo, C.E.; Greenberg, R.A.; Flaherty, K.T.; Rathmell, W.K.; Keith, B.; Simon, M.C.; Nathanson, K.L. HIF-α Effects on c-Myc Distinguish Two Subtypes of Sporadic VHL-Deficient Clear Cell Renal Carcinoma. Cancer Cell, 2008, 14, 435–446.
[12] Sonveaux, P.; Végran, F.; Schroeder, T.; Wergin, M.C.; Verrax, J.; Rabbani, Z.N.; De Saedeleer, C.J.; Kennedy, K.M.; Diepart, C.; Jordan, B.F.; Kelley, M.J.; Gallez, B.; Wahl, M.L.; Feron, O.; Dewhirst, M.W. Targeting Lactate-Fueled Respiration Selectively Kills Hypoxic Tumor Cells in Mice. J. Clin. Invest., 2008, 118, 3930–3942.
[13] Corrado, C.; Fontana, S. Hypoxia and HIF Signaling: One Axis with Divergent Effects. Int. J. Mol. Sci., 2020, 21, 1–17.
[14] Paltoglou, S.; Roberts, B.J. HIF-1α and EPAS Ubiquitination Mediated by the VHL Tumour Suppressor Involves Flexibility in the Ubiquitination Mechanism, Similar to Other RING E3 Ligases. Oncogene, 2007, 26, 604–609.
[15] Schönberger, T.; Fandrey, J.; Prost-Fingerle, K. Ways into Understanding HIF Inhibition. Cancers (Basel)., 2021, 13, 1–16.
[16] Wang, G.L.; Jiang, B.H.; Rue, E.A.; Semenza, G.L. Hypoxia-Inducible Factor 1 Is a Basic-Helix-Loop-Helix-PAS Heterodimer Regulated by Cellular O2 Tension. Proc. Natl. Acad. Sci. U. S. A., 1995, 92, 5510–5514.
[17] Jiang, B.H.; Zheng, J.Z.; Leung, S.W.; Roe, R.; Semenza, G.L. Transactivation and Inhibitory Domains of Hypoxia-Inducible Factor 1α: Modulation of Transcriptional Activity by Oxygen Tension. J. Biol. Chem., 1997, 272, 19253–19260.
[18] Young, A.C.; Craven, R.A.; Cohen, D.; Taylor, C.; Booth, C.; Harnden, P.; Cairns, D.A.; Astuti, D.; Gregory, W.; Maher, E.R.; Knowles, M.A.; Joyce, A.; Selby, P.J.; Banks, R.E. Analysis of VHL Gene Alterations and Their Relationship to Clinical Parameters in Sporadic Conventional Renal Cell Carcinoma. Clin. Cancer Res., 2009, 15, 7582–7592.
[19] Glasker, S.; Vergauwen, E.; Koch, C.A.; Kutikov, A.; Vortmeyer, A.O. Von Hippel-Lindau Disease : Current Challenges and Future Prospects. 2020, 5669–5690.
[20] Nickerson, M.L.; Jaeger, E.; Shi, Y.; Durocher, J.A.; Mahurkar, S.; Zaridze, D.; Matveev, V.; Janout, V.; Kollarova, H.; Bencko, V.; Navratilova, M.; Szeszenia-Dabrowska, N.; Mates, D.; Mukeria, A.; Holcatova, I.; Schmidt, L.S.; Toro, J.R.; Karami, S.; Hung, R.; Gerard, G.F.; Linehan, W.M.; Merino, M.; Zbar, B.; Boffetta, P.; Brennan, P.; Rothman, N.; Chow, W.H.; Waldman, F.M.; Moore, L.E. Improved Identification of von Hippel-Lindau Gene Alterations in Clear Cell Renal Tumors. Clin. Cancer Res., 2008, 14, 4726–4734.
[21] Loboda, A.; Jozkowicz, A.; Dulak, J. HIF-1 and HIF-2 Transcription Factors--Similar but Not Identical. Mol. Cells, 2010, 29, 435–442.
[22] Hoefflin, R.; Harlander, S.; Schäfer, S.; Metzger, P.; Kuo, F.; Schönenberger, D.; Adlesic, M.; Peighambari, A.; Seidel, P.; Chen, C. yi; Consenza-Contreras, M.; Jud, A.; Lahrmann, B.; Grabe, N.; Heide, D.; Uhl, F.M.; Chan, T.A.; Duyster, J.; Zeiser, R.; Schell, C.; Heikenwalder, M.; Schilling, O.; Hakimi, A.A.; Boerries, M.; Frew, I.J. HIF-1α and HIF-2α Differently Regulate Tumour Development and Inflammation of Clear Cell Renal Cell Carcinoma in Mice. Nat. Commun., 2020, 11.
[23] Akhtar, M.; Al-Bozom, I.A.; Hussain, T. Al. Molecular and Metabolic Basis of Clear Cell Carcinoma of the Kidney. Adv. Anat. Pathol., 2018, 25, 189–196.
[24] Masson, N.; Ratcliffe, P.J. Hypoxia Signaling Pathways in Cancer Metabolism: The Importance of Co-Selecting Interconnected Physiological Pathways. Cancer Metab., 2014, 2, 1–17.
[25] Mailloux, R.J. An Update on Methods and Approaches for Interrogating Mitochondrial Reactive Oxygen Species Production. Redox Biol., 2021, 45, 102044.
[26] Sosa, V.; Moliné, T.; Somoza, R.; Paciucci, R.; Kondoh, H.; LLeonart, M.E. Oxidative Stress and Cancer: An Overview. Ageing Res. Rev., 2013, 12, 376–390.
[27] Basak, P.; Sadhukhan, P.; Sarkar, P.; Sil, P.C. Perspectives of the Nrf-2 Signaling Pathway in Cancer Progression and Therapy. Toxicol. Reports, 2017, 4, 306–318.
[28] Krajka-Kuźniak, V.; Paluszczak, J.; Baer-Dubowska, W. The Nrf2-ARE Signaling Pathway: An Update on Its Regulation and Possible Role in Cancer Prevention and Treatment. Pharmacol. Reports, 2017, 69, 393–402.
[29] Namani, A.; Li, Y.; Wang, X.J.; Tang, X. Modulation of NRF2 Signaling Pathway by Nuclear Receptors: Implications for Cancer. Biochim. Biophys. Acta - Mol. Cell Res., 2014, 1843, 1875–1885.
[30] Tong, K.I.; Padmanabhan, B.; Kobayashi, A.; Shang, C.; Hirotsu, Y.; Yokoyama, S.; Yamamoto, M. Different Electrostatic Potentials Define ETGE and DLG Motifs as Hinge and Latch in Oxidative Stress Response. Mol. Cell. Biol., 2007, 27, 7511–7521.
[31] Bensasson, R. V.; Zoete, V.; Dinkova-Kostova, A.T.; Talalay, P. Two-Step Mechanism of Induction of the Gene Expression of a Prototypic Cancer-Protective Enzyme by Diphenols. Chem. Res. Toxicol., 2008, 21, 805–812.
[32] Fourquet, S.; Guerois, R.; Biard, D.; Toledano, M.B. Activation of NRF2 by Nitrosative Agents and H2O2 Involves KEAP1 Disulfide Formation. J. Biol. Chem., 2010, 285, 8463–8471.
[33] Hong, F.; Freeman, M.L.; Liebler, D.C. Identification of Sensor Cysteines in Human Keap1 Modified by the Cancer Chemopreventive Agent Sulforaphane. Chem. Res. Toxicol., 2005, 18, 1917–1926.
[34] Chartoumpekis, D.V.; Wakabayashi, N.; Kensler, T.W. Keap1/Nrf2 Pathway in the Frontiers of Cancer and Non-Cancer Cell Metabolism. Biochem. Soc. Trans., 2015, 43, 639–644.
[35] Pelicano, H.; Carney, D.; Huang, P. ROS Stress in Cancer Cells and Therapeutic Implications. Drug Resist. Updat., 2004, 7, 97–110.
[36] Fabrizio, F.P.; Costantini, M.; Copetti, M.; Sparaneo, A.; Fontana, A.; Poeta, L.; Gallucci, M.; Sentinelli, S.; Graziano, P.; Parente, P.; Pompeo, V.; De, L.; Simone, G.; Papalia, R.; Picardo, F.; Balsamo, T.; Paranita, F.; Muscarella, L.A.; Fazio, V. Keap1/Nrf2 Pathway in Kidney Cancer: Frequent Methylation of Keap1 Gene Promoter in Clear Renal Cell Carcinoma. Oncotarget, 2016, 8, 11187–11198.
[37] Reszka, E.; Jablonowski, Z.; Wieczorek, E.; Jablonska, E.; Krol, M.B.; Gromadzinska, J.; Grzegorczyk, A.; Sosnowski, M.; Wasowicz, W. Polymorphisms of NRF2 and NRF2 Target Genes in Urinary Bladder Cancer Patients. J. Cancer Res. Clin. Oncol., 2014, 140, 1723–1731.
[38] Mihailovic, S.; Coric, V.; Radic, T.; Radojevic, A.S.; Matic, M.; Dragicevic, D.; Djokic, M.; Vasic, V.; Dzamic, Z.; Simic, T.; Hadzi-djokic, J.; Ercegovac, M.P. The Association of Polymorphisms in Nrf2 and Genes Involved in Redox Homeostasis in the Development and Progression of Clear Cell Renal Cell Carcinoma. 2021, 2021.
[39] Ji, S.; Xiong, Y.; Zhao, X.; Liu, Y.; Yu, L.Q. Effect of the Nrf2-Are Signaling Pathway on Biological Characteristics and Sensitivity to Sunitinib in Renal Cell Carcinoma. Oncol. Lett., 2019, 17, 5175–5186.
[40] Pljesa-Ercegovac, M.; Savic-Radojevic, A.; Coric, V.; Radic, T.; Simic, T. Glutathione Transferase Genotypes May Serve as Determinants of Risk and Prognosis in Renal Cell Carcinoma. BioFactors, 2020, 46, 229–238.
[41] Hayes, J.D.; McMahon, M. NRF2 and KEAP1 Mutations: Permanent Activation of an Adaptive Response in Cancer. Trends Biochem. Sci., 2009, 34, 176–188.
[42] Bartolini, D.; Galli, F. The Functional Interactome of GSTP: A Regulatory Biomolecular Network at the Interface with the Nrf2 Adaption Response to Oxidative Stress. J. Chromatogr. B Anal. Technol. Biomed. Life Sci., 2016, 1019, 29–44.
[43] Meitzler, J.L.; Konaté, M.M.; Doroshow, J.H. Hydrogen Peroxide-Producing NADPH Oxidases and the Promotion of Migratory Phenotypes in Cancer. Arch. Biochem. Biophys., 2019, 675, 108076.
[44] Figueira, T.R.; Barros, M.H.; Camargo, A.A.; Castilho, R.F.; Ferreira, J.C.B.; Kowaltowski, A.J.; Sluse, F.E.; Souza-Pinto, N.C.; Vercesi, A.E. Mitochondria as a Source of Reactive Oxygen and Nitrogen Species: From Molecular Mechanisms to Human Health. Antioxidants Redox Signal., 2013, 18, 2029–2074.
[45] Wang, Y.; Branicky, R.; Noë, A.; Hekimi, S. Superoxide Dismutases: Dual Roles in Controlling ROS Damage and Regulating ROS Signaling. J. Cell Biol., 2018, 217, 1915–1928.
[46] Kumar, A.; Vaish, M.; Karuppagounder, S.S.; Gazaryan, I.; Cave, J.W.; Starkov, A.A.; Anderson, E.T.; Zhang, S.; Pinto, J.T.; Rountree, A.M.; Wang, W.; Sweet, I.R.; Ratan, R.R. HIF1α Stabilization in Hypoxia Is Not Oxidant-Initiated. Elife, 2021, 10, 1–23.
[47] Jobim, M.L.; Azzolin, V.F.; Assmann, C.E.; Morsch, V.M.M.; da Cruz, I.B.M.; de Freitas Bauermann, L. Superoxide-Hydrogen Peroxide Imbalance Differentially Modulates the Keratinocytes Cell Line (HaCaT) Oxidative Metabolism via Keap1-Nrf2 Redox Signaling Pathway. Mol. Biol. Rep., 2019, 46, 5785–5793.
[48] Miller, A.F. Superoxide Dismutases: Ancient Enzymes and New Insights. FEBS Lett., 2012, 586, 585–595.
[49] Raghunath, A.; Sundarraj, K.; Nagarajan, R.; Arfuso, F.; Bian, J.; Kumar, A.P.; Sethi, G.; Perumal, E. Antioxidant Response Elements: Discovery, Classes, Regulation and Potential Applications. Redox Biol., 2018, 17, 297–314.
[50] Hart, P.C.; Mao, M.; Abreu, A.L. de; Fricano, K.A.-; Ekoue, D.N.; Ganini, D.; Kajdacsy-Balla, A.; Diamond, A.M.; Minshall, R.D.; Consolaro, M.E.L.; Santos, J.H.; Bonini, M.G. MnSOD Upregulation Sustains the Warburg Effect via Mitochondrial ROS and AMPK-Dependent Signaling in Cancer Peter. Nat. Commun., 2015, 6, 6053.
[51] Dasgupta, J.; Subbaram, S.; Connor, K.; Rodriguez, A.; Tirosh, O.; Beckman, J.; Jourd’Heuil, D.; Melendez, J. Manganese Superoxide Dismutase Protects from TNF-?–Induced Apoptosis by Increasing the Steady-State Production of H2O2. Antioxidants Redox Signal., 2006, 8, 1295–1305.
[52] Ekoue, D.; He, C.; Diamond, A.; Bonini, M. Manganese Superoxide Dismutase and Glutathione Peroxidase-1 Contribute to the Rise and Fall of Mitochondrial Reactive Oxygen Species Which Drive Oncogenesis. Biochim. Biophys. Acta, 2017, 1858, 628–632.
[53] Lubos, E.; Loscalzo, J.; Handy, D.E. Glutathione Peroxidase-1 in Health and Disease: From Molecular Mechanisms to Therapeutic Opportunities. Antioxidants Redox Signal., 2011, 15, 1957–1997.
[54] Brigelius-Flohé, R.; Kipp, A. Glutathione Peroxidases in Different Stages of Carcinogenesis. Biochim. Biophys. Acta - Gen. Subj., 2009, 1790, 1555–1568.
[55] Cheng, Y.; Xu, T.; Li, S.; Ruan, H. GPX1, a Biomarker for the Diagnosis and Prognosis of Kidney Cancer, Promotes the Progression of Kidney Cancer. Aging (Albany. NY)., 2019, 11, 12165–12176.