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GSTM2 is a key molecular determinant of resistance to SG-ARIs

Oncogene volume 41, pages 4498–4511 (2022)Cite this article

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Abstract

Prostate cancer (PCa) continues to threaten men’s health, and treatment targeting the androgen receptor (AR) pathway is the major therapy for PCa patients. Several second-generation androgen receptor inhibitors (SG-ARIs), including enzalutamide (ENZ), apalutamide (APA) and darolutamide (DARO), have been developed to better block the activity of AR. Unavoidably, emergence of resistance to these novel drugs still persists. Herein, we identified glutathione S-transferase Mu 2 (GSTM2) as an important determinant in the acquisition of resistance to SG-ARIs. Elevated GSTM2 was detected in enzalutamide-resistant (ENZ-R) PCa, and overexpression of GSTM2 in naïve enzalutamide-sensitive (ENZ-S) cells effectively transformed them to ENZ-R PCa. Aryl hydrocarbon receptor (AhR), the upstream transcription factor, was implicated in the overexpression of GSTM2 in ENZ-R cells. Mechanistically, GSTM2 antagonized the effect of ENZ by rescuing cells from oxidative stress-associated damage and activation of p38 MAPK pathway. Surprisingly, high GSTM2 levels also associated with cross-resistance to APA and DARO. Taking together, these results provide new insight to ameliorate resistance to SG-ARIs and improve treatment outcome.

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Fig. 1: Integrative analysis of RNA-seq and ATAC-seq indicates critical role of GSTM2 in ENZ-R PCa.
Fig. 2: Targeting GSTM2 overcomes resistance to ENZ.
Fig. 3: AhR is associated with ENZ-R phenotype caused by GSTM2.
Fig. 4: ENZ-R cells rely on endogenous remedy to survive OS-associated damage incurred by treatment.
Fig. 5: GSTM2 rescues cell fate by inhibiting the p38 MAPK pathway.
Fig. 6: GSTM2 and cross-resistance to SG-ARIs.
Fig. 7: In vivo 22Rv1 xenograft experiment.
Fig. 8: Clinical evidence of GSTM2 and the salvage system of OS damage in the acquisition of resistance to SG-ARIs.

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    Article  PubMed  Google Scholar 

  2. Teo MY, Rathkopf DE, Kantoff P. Treatment of advanced prostate cancer. Annu Rev Med. 2019;70:479–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Coutinho I, Day TK, Tilley WD, Selth LA. Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence. Endocr Relat Cancer. 2016;23:T179–t197.

    Article  CAS  PubMed  Google Scholar 

  4. Higano C. Enzalutamide, apalutamide, or darolutamide: are apples or bananas best for patients?. Nat Rev Urol. 2019;16:335–6.

    Article  PubMed  Google Scholar 

  5. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.

    Article  CAS  PubMed  Google Scholar 

  6. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408–18.

    Article  CAS  PubMed  Google Scholar 

  7. Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380:1235–46.

    Article  CAS  PubMed  Google Scholar 

  8. 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;51:1320–8.

    Article  CAS  PubMed  Google Scholar 

  9. Kumar B, Koul S, Khandrika L, Meacham RB, Koul HK. Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res. 2008;68:1777–85.

    Article  CAS  PubMed  Google Scholar 

  10. Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell. 2020;38:167–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sies H, Berndt C, Jones DP. Oxidative stress. Annu Rev Biochem. 2017;86:715–48.

    Article  CAS  PubMed  Google Scholar 

  12. Neha K, Haider MR, Pathak A, Yar MS. Medicinal prospects of antioxidants: a review. Eur J Med Chem. 2019;178:687–704.

    Article  CAS  PubMed  Google Scholar 

  13. Allocati N, Masulli M, Di C. Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases. Oncogenesis. 2018;7:8.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhou SG, Wang P, Pi RB, Gao J, Fu JJ, Fang J, et al. Reduced expression of GSTM2 and increased oxidative stress in spontaneously hypertensive rat. Mol Cell Biochem. 2008;309:99–107.

    Article  CAS  PubMed  Google Scholar 

  15. Han I, Jeong SJ, Lee HJ, Koh W, Lee HJ, Lee EO, et al. Proteomic analysis of mesenchymal stem-like cells derived from ovarian teratoma: potential role of glutathione S-transferase M2 in ovarian teratoma. Proteomics. 2011;11:352–60.

    Article  CAS  PubMed  Google Scholar 

  16. Guo E, Wei H, Liao X, Wu L, Zeng X. Clinical significance and biological mechanisms of glutathione S-transferase mu gene family in colon adenocarcinoma. BMC Med Genet. 2020;21:130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Andonova IE, Justenhoven C, Winter S, Hamann U, Baisch C, Rabstein S, et al. No evidence for glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 in breast cancer risk. Breast Cancer Res Treat. 2010;121:497–502.

    Article  CAS  PubMed  Google Scholar 

  18. Tang SC, Wu CH, Lai CH, Sung WW, Yang WJ, Tang LC, et al. Glutathione S-transferase mu2 suppresses cancer cell metastasis in non-small cell lung cancer. Mol Cancer Res. 2013;11:518–29.

    Article  CAS  PubMed  Google Scholar 

  19. Peng L, Zhuang L, Lin K, Yao Y, Zhang Y, Arumugam T, et al. Downregulation of GSTM2 enhances gemcitabine chemosensitivity of pancreatic cancer in vitro and in vivo. Pancreatology. 2021;21:115–23.

    Article  CAS  PubMed  Google Scholar 

  20. Buenrostro JD, Wu B, Chang HY, Greenleaf WJ. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr Protoc Mol Biol. 2015;109:21.29.1–9.

    Article  Google Scholar 

  21. Li C, Lanman NA, Kong Y, He D, Mao F, Farah E, et al. Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance. J Biol Chem. 2020;295:5470–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ricci G, De Maria F, Antonini G, Turella P, Bullo A, Stella L, et al. 7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs. J Biol Chem. 2005;280:26397–405.

    Article  CAS  PubMed  Google Scholar 

  23. Bhattacharjee P, Paul S, Banerjee M, Patra D, Banerjee P, Ghoshal N, et al. Functional compensation of glutathione S-transferase M1 (GSTM1) null by another GST superfamily member, GSTM2. Sci Rep. 2013;3:2704.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Sagar YK. Does glutathione transferase loading into exosomes from prostate cancer cells influence progression? 2016. https://eprints.qut.edu.au/98015/.

  25. Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2013;73:483–9.

    Article  CAS  PubMed  Google Scholar 

  26. Zhao L, Au JL, Wientjes MG. Comparison of methods for evaluating drug-drug interaction. Front Biosci. 2010;2:241–9.

    Google Scholar 

  27. Hayes JD, Dinkova-Kostova AT, McMahon M. Cross-talk between transcription factors AhR and Nrf2: lessons for cancer chemoprevention from dioxin. Toxicol Sci. 2009;111:199–201.

    Article  CAS  PubMed  Google Scholar 

  28. Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol. 2019;19:184–97.

    Article  CAS  PubMed  Google Scholar 

  29. Shiota M, Yokomizo A, Tada Y, Inokuchi J, Kashiwagi E, Masubuchi D, et al. Castration resistance of prostate cancer cells caused by castration-induced oxidative stress through Twist1 and androgen receptor overexpression. Oncogene. 2010;29:237–50.

    Article  CAS  PubMed  Google Scholar 

  30. Dolado I, Swat A, Ajenjo N, De Vita G, Cuadrado A, Nebreda AR. p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell. 2007;11:191–205.

    Article  CAS  PubMed  Google Scholar 

  31. Canovas B, Nebreda AR. Diversity and versatility of p38 kinase signalling in health and disease. Nat Rev Mol Cell Biol. 2021;22:346–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhao J, Ning S, Lou W, Yang JC, Armstrong CM, Lombard AP, et al. Cross-resistance among next-generation antiandrogen drugs through the AKR1C3/AR-V7 axis in advanced prostate cancer. Mol Cancer Ther. 2020;19:1708–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72:1494–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25. https://pubmed.ncbi.nlm.nih.gov/26544944/.

  36. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Abida W, Cyrta J, Heller G, Prandi D, Armenia J, Coleman I, et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc Natl Acad Sci USA. 2019;116:11428–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hamdy FC, Donovan JL, Lane JA, Mason M, Metcalfe C, Holding P, et al. 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375:1415–24.

    Article  PubMed  Google Scholar 

  39. Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Alumkal JJ, Sun D, Lu E, Beer TM, Thomas GV, Latour E, et al. Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance. Proc Natl Acad Sci USA. 2020;117:12315–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. He Y, Wei T, Ye Z, Orme JJ, Lin D, Sheng H, et al. A noncanonical AR addiction drives enzalutamide resistance in prostate cancer. Nat Commun. 2021;12:1521.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhao SG, Chen WS, Li H, Foye A, Zhang M, Sjöström M, et al. The DNA methylation landscape of advanced prostate cancer. Nat Genet. 2020;52:778–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Davies A, Nouruzi S, Ganguli D, Namekawa T, Thaper D, Linder S, et al. An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer. Nat Cell Biol. 2021;23:1023–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang Z, Zhou C, Li X, Barnes SD, Deng S, Hoover E, et al. Loss of CHD1 promotes heterogeneous mechanisms of resistance to AR-targeted therapy via chromatin dysregulation. Cancer Cell. 2020;37:584–.e11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gibbons JA, Ouatas T, Krauwinkel W, Ohtsu Y, van der Walt JS, Beddo V, et al. Clinical pharmacokinetic studies of enzalutamide. Clin Pharmacokinet. 2015;54:1043–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. de Vries R, Jacobs F, Mannens G, Snoeys J, Cuyckens F, Chien C, et al. Apalutamide absorption, metabolism, and excretion in healthy men, and enzyme reaction in human hepatocytes. Drug Metab Dispos. 2019;47:453–64.

    Article  PubMed  Google Scholar 

  47. Ji C, Guha M, Zhu X, Whritenour J, Hemkens M, Tse S, et al. Enzalutamide and apalutamide: in vitro chemical reactivity studies and activity in a mouse drug allergy model. Chem Res Toxicol. 2020;33:211–22.

    Article  CAS  PubMed  Google Scholar 

  48. Liu C, Lou W, Zhu Y, Yang JC, Nadiminty N, Gaikwad NW, et al. Intracrine androgens and AKR1C3 activation confer resistance to enzalutamide in prostate cancer. Cancer Res. 2015;75:1413–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hayer A, Shao L, Chung M, Joubert LM, Yang HW, Tsai FC, et al. Engulfed cadherin fingers are polarized junctional structures between collectively migrating endothelial cells. Nat Cell Biol. 2016;18:1311–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The research is generously supported by NIH R01 CA157429 (XL), R01 CA196634 (XL), R01 CA264652 (XL), R01 CA256893 (XL). This research is also supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, Redox Metabolism, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). We thanks Dr. Alumkal Joshi for the generous sharing of the RNA-seq raw data, and Eleanor Erikson for the critical reading and editing of the manuscript.

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Authors and Affiliations

  1. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, 40536, USA

    Chaohao Li, Fengyi Mao, Xiongjian Rao, Jinghui Liu, Chrispus M. Ngule, Zhuangzhuang Zhang, Yanquan Zhang, Yifan Kong & Xiaoqi Liu

  2. Department of Biostatistics, University of Kentucky, Lexington, KY, 40536, USA

    Jinpeng Liu, Daheng He & Chi Wang

  3. Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA

    Jinpeng Liu, Daheng He, Chi Wang & Xiaoqi Liu

  4. Department of Biomedical Informatics, The Ohio State University, Columbus, OH, 43210, USA

    Yue Zhao & Lang Li

  5. Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA

    Nadia A. Lanman

  6. Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA

    Nadia A. Lanman

  7. Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA

    Majid Kazemian & Elia Farah

  8. Department of Computer Science, Purdue University, West Lafayette, IN, 47907, USA

    Majid Kazemian

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Contributions

XL: conceptualization; CL and XL: project administration; CL and XL: investigation; CL: validation and visualization; CL, JPL, DH, YZ, NAL, MK and XL: methodology; CL, JPL, DH, YZ and NAL: data curation; CL, JPL, DH, YZ and NAL: formal analysis; XR, JL, ZZ, YQZ, LL, CW and XL: supervision; FM, XR, EF, CMN, YK, LL, CW and XL: resources; JPL, DH, YZ, NAL and XL: software; XL: funding acquisition; CL, JPL and DH: writing—original draft; XL: writing—review and editing.

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Correspondence to Xiaoqi Liu.

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Li, C., Liu, J., He, D. et al. GSTM2 is a key molecular determinant of resistance to SG-ARIs. Oncogene 41, 4498–4511 (2022). https://doi.org/10.1038/s41388-022-02444-1

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