Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Critical role of antioxidant programs in enzalutamide-resistant prostate cancer

Oncogene volume 42, pages 2347–2359 (2023)Cite this article

Subjects

Abstract

Therapy resistance to second-generation androgen receptor (AR) antagonists, such as enzalutamide, is common in patients with advanced prostate cancer (PCa). To understand the metabolic alterations involved in enzalutamide resistance, we performed metabolomic, transcriptomic, and cistromic analyses of enzalutamide-sensitive and -resistant PCa cells, xenografts, patient-derived organoids, patient-derived explants, and tumors. We noted dramatically higher basal and inducible levels of reactive oxygen species (ROS) in enzalutamide-resistant PCa and castration-resistant PCa (CRPC), in comparison to enzalutamide-sensitive PCa cells or primary therapy-naive tumors respectively. Unbiased metabolomic evaluation identified that glutamine metabolism was consistently upregulated in enzalutamide-resistant PCa cells and CRPC tumors. Stable isotope tracing studies suggest that this enhanced glutamine metabolism drives an antioxidant program that allows these cells to tolerate higher basal levels of ROS. Inhibition of glutamine metabolism with either a small-molecule glutaminase inhibitor or genetic knockout of glutaminase enhanced ROS levels, and blocked the growth of enzalutamide-resistant PCa. The critical role of compensatory antioxidant pathways in maintaining enzalutamide-resistant PCa cells was validated by targeting another antioxidant program driver, ferredoxin 1. Taken together, our data identify a metabolic need to maintain antioxidant programs and a potentially targetable metabolic vulnerability in enzalutamide-resistant PCa.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Enzalutamide induces ROS in EnzS cells in vitro and in patient tumors ex vivo.
Fig. 2: EnzR cells and antiandrogen-treated CRPC tumors have increased basal and inducible ROS.
Fig. 3: EnzR cells and CRPC tumors have enhanced glutamine metabolism.
Fig. 4: EnzR cells are vulnerable to glutamine blockade.
Fig. 5: EnzR cells are vulnerable to ferredoxin blockade.

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and corresponding supplementary information files. Any additional datasets generated during and/or analyzed during this study are available from the corresponding author upon reasonable request.

References

  1. 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 

  2. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10:33–9.

    Article  PubMed  Google Scholar 

  3. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Prostate Cancer Trialists Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists’ Collaborative Group. Lancet. 2000;355:1491–8.

  5. Huggins C. Prostatic cancer treated by orchiectomy; the five year results. J Am Med Assoc. 1946;131:576–81.

    Article  CAS  PubMed  Google Scholar 

  6. Liu J, Geller J, Albert J, Kirshner M. Acute effects of testicular and adrenal cortical blockade on protein synthesis and dihydrotestosterone content of human prostate tissue. J Clin Endocrinol Metab. 1985;61:129–33.

    Article  CAS  PubMed  Google Scholar 

  7. Mercader M, Sengupta S, Bodner BK, Manecke RG, Cosar EF, Moser MT, et al. Early effects of pharmacological androgen deprivation in human prostate cancer. BJU Int. 2007;99:60–7.

    Article  CAS  PubMed  Google Scholar 

  8. Mohler JL, Gregory CW, Ford OH 3rd, Kim D, Weaver CM, Petrusz P, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10:440–8.

    Article  CAS  PubMed  Google Scholar 

  9. Montironi R, Magi-Galluzzi C, Muzzonigro G, Prete E, Polito M, Fabris G. Effects of combination endocrine treatment on normal prostate, prostatic intraepithelial neoplasia, and prostatic adenocarcinoma. J Clin Pathol. 1994;47:906–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mostaghel EA, Page ST, Lin DW, Fazli L, Coleman IM, True LD, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007;67:5033–41.

    Article  CAS  PubMed  Google Scholar 

  11. Ohlson N, Wikström P, Stattin P, Bergh A. Cell proliferation and apoptosis in prostate tumors and adjacent non-malignant prostate tissue in patients at different time-points after castration treatment. Prostate. 2005;62:307–15.

    Article  PubMed  Google Scholar 

  12. Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021;39:2294–303.

    Article  CAS  PubMed  Google Scholar 

  13. Fizazi K, Shore ND, Smith MR, Ramos R, Jones RJ, Niegisch G, et al. Efficacy and safety outcomes of darolutamide in patients with nonmetastatic castration-resistant prostate cancer with comorbidities and concomitant medications from ARAMIS. J Clin Oncol. 2022;40:256.

    Article  Google Scholar 

  14. Fizazi K, Shore ND, Tammela T, Ulys A, Vjaters E, Polyakov S, et al. ARAMIS: Efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37:140.

    Article  Google Scholar 

  15. Gourd E. Apalutamide shows efficacy in prostate cancer. Lancet Oncol. 2018;19:e149.

    Article  PubMed  Google Scholar 

  16. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2018;378:2465–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Komura K, Fujiwara Y, Uchimoto T, Saito K, Tanda N, Matsunaga T, et al. Comparison of Radiographic Progression-Free Survival and PSA Response on Sequential Treatment Using Abiraterone and Enzalutamide for Newly Diagnosed Castration-Resistant Prostate Cancer: A Propensity Score Matched Analysis from Multicenter Cohort. J Clin Med. 2019;8:1251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Farber S. Some observations on the effect of folic acid antagonists on acute leukemia and other forms of incurable cancer. Blood. 1949;4:160–7.

    Article  CAS  PubMed  Google Scholar 

  20. Noordhuis P, Holwerda U, Van der Wilt CL, Van Groeningen CJ, Smid K, Meijer S, et al. 5-Fluorouracil incorporation into RNA and DNA in relation to thymidylate synthase inhibition of human colorectal cancers. Ann Oncol. 2004;15:1025–32.

    Article  CAS  PubMed  Google Scholar 

  21. Werkheiser WC. Specific Binding of 4-Amino Folic Acid Analogues by Folic Acid Reductase. J Biol Chem. 1961;236:888–93.

    Article  CAS  Google Scholar 

  22. Yang Z, Wang D, Johnson JK, Pascal LE, Takubo K, Avula R, et al. A Novel Small Molecule Targets Androgen Receptor and Its Splice Variants in Castration-Resistant Prostate Cancer. Mol Cancer Ther. 2020;19:75–88.

    Article  CAS  PubMed  Google Scholar 

  23. Gillis JL, Hinneh JA, Ryan NK, Irani S, Moldovan M, Quek LE, et al. A feedback loop between the androgen receptor and 6-phosphogluoconate dehydrogenase (6PGD) drives prostate cancer growth. Elife. 2021;10:e62592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Geng H, Xue C, Mendonca J, Sun XX, Liu Q, Reardon PN, et al. Interplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy. Nat Commun. 2018;9:4972.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Poluri RTK, Paquette V, P Allain É, Lafront C, Joly-Beauparlant C, Weidmann C, et al. KLF5 and NFYA factors as novel regulators of prostate cancer cell metabolism. Endocr Relat Cancer. 2021;28:257–71.

    Article  CAS  PubMed  Google Scholar 

  26. Sappington DR, Siegel ER, Hiatt G, Desai A, Penney RB, Jamshidi-Parsian A, et al. Glutamine drives glutathione synthesis and contributes to radiation sensitivity of A549 and H460 lung cancer cell lines. Biochim Biophys Acta. 2016;1860:836–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Stelloo S, Nevedomskaya E, Kim Y, Hoekman L, Bleijerveld OB, Mirza T, et al. Endogenous androgen receptor proteomic profiling reveals genomic subcomplex involved in prostate tumorigenesis. Oncogene. 2018;37:313–22.

    Article  CAS  PubMed  Google Scholar 

  28. Ramanand SG, Chen Y, Yuan J, Daescu K, Lambros MB, Houlahan KE, et al. The landscape of RNA polymerase II-associated chromatin interactions in prostate cancer. J Clin Investig. 2020;130:3987–4005.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Taberlay PC, Achinger-Kawecka J, Lun AT, Buske FA, Sabir K, Gould CM, et al. Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations. Genome Res. 2016;26:719–31.

    Article  CAS  Google Scholar 

  30. Birkenmeier G, Stegemann C, Hoffmann R, GĂĽnther R, Huse K, Birkemeyer C. Posttranslational modification of human glyoxalase 1 indicates redox-dependent regulation. PLoS One. 2010;5:e10399.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Fratelli M, Demol H, Puype M, Casagrande S, Villa P, Eberini I, et al. Identification of proteins undergoing glutathionylation in oxidatively stressed hepatocytes and hepatoma cells. Proteomics. 2003;3:1154–61.

    Article  CAS  PubMed  Google Scholar 

  32. Hollenbach M, Hintersdorf A, Huse K, Sack U, Bigl M, Groth M, et al. Ethyl pyruvate and ethyl lactate down-regulate the production of pro-inflammatory cytokines and modulate expression of immune receptors. Biochem Pharmacol. 2008;76:631–44.

    Article  CAS  PubMed  Google Scholar 

  33. Centenera MM, Hickey TE, Jindal S, Ryan NK, Ravindranathan P, Mohammed H, et al. A patient-derived explant (PDE) model of hormone-dependent cancer. Mol Oncol. 2018;12:1608–22.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kregel S, Chen JL, Tom W, Krishnan V, Kach J, Brechka H, et al. Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer. Oncotarget. 2016;7:26259–74.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bishop JL, Thaper D, Vahid S, Davies A, Ketola K, Kuruma H, et al. The Master Neural Transcription Factor BRN2 Is an Androgen Receptor-Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer. Cancer Discov. 2017;7:54–71.

    Article  CAS  PubMed  Google Scholar 

  36. Liu C, Lou W, Zhu Y, Nadiminty N, Schwartz CT, Evans CP, et al. Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer. Clin Cancer Res. 2014;20:3198–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Luengo A, Abbott KL, Davidson SM, Hosios AM, Faubert B, Chan SH, et al. Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer. Nat Commun. 2019;10:5604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tsvetkov P, Detappe A, Cai K, Keys HR, Brune Z, Ying W, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol. 2019;15:681–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tam NN, Gao Y, Leung YK, Ho SM. Androgenic regulation of oxidative stress in the rat prostate: involvement of NAD(P)H oxidases and antioxidant defense machinery during prostatic involution and regrowth. Am J Pathol. 2003;163:2513–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lu JP, Monardo L, Bryskin I, Hou ZF, Trachtenberg J, Wilson BC, et al. Androgens induce oxidative stress and radiation resistance in prostate cancer cells though NADPH oxidase. Prostate Cancer Prostatic Dis. 2010;13:39–46.

    Article  CAS  PubMed  Google Scholar 

  41. Pinthus JH, Bryskin I, Trachtenberg J, Lu JP, Singh G, Fridman E, et al. Androgen induces adaptation to oxidative stress in prostate cancer: implications for treatment with radiation therapy. Neoplasia. 2007;9:68–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Marcias G, Erdmann E, Lapouge G, Siebert C, Barthélémy P, Duclos B, et al. Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line. Hum Mutat. 2010;31:74–80.

    Article  CAS  PubMed  Google Scholar 

  43. White MA, Lin C, Rajapakshe K, Dong J, Shi Y, Tsouko E, et al. Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer. Mol Cancer Res. 2017;15:1017–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Xu L, Yin Y, Li Y, Chen X, Chang Y, Zhang H, et al. A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer. Proc Natl Acad Sci USA. 2021;118:e2012748118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Galan-Cobo A, Sitthideatphaiboon P, Qu X, Poteete A, Pisegna MA, Tong P, et al. LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS-Mutant Lung Adenocarcinoma. Cancer Res. 2019;79:3251–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13:890–901.

    Article  CAS  PubMed  Google Scholar 

  47. McBrayer SK, Mayers JR, DiNatale GJ, Shi DD, Khanal J, Chakraborty AA, et al. Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell. 2018;175:101–116.e25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Myint ZW, Sun RC, Hensley PJ, James AC, Wang P, Strup SE, et al. Evaluation of Glutaminase Expression in Prostate Adenocarcinoma and Correlation with Clinicopathologic Parameters. Cancers. 2021;13:2157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kirshner JR, He S, Balasubramanyam V, Kepros J, Yang CY, Zhang M, et al. Elesclomol induces cancer cell apoptosis through oxidative stress. Mol Cancer Ther. 2008;7:2319–27.

    Article  CAS  PubMed  Google Scholar 

  50. O’Day S, Gonzalez R, Lawson D, Weber R, Hutchins L, Anderson C, et al. Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma. J Clin Oncol. 2009;27:5452–8.

    Article  PubMed  Google Scholar 

  51. Reitzer LJ, Wice BM, Kennell D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem. 1979;254:2669–76.

    Article  CAS  PubMed  Google Scholar 

  52. Wagner A, Marc A, Engasser JM, Einsele A. Growth and metabolism of human tumor kidney cells on galactose and glucose. Cytotechnology. 1991;7:7–13.

    Article  CAS  PubMed  Google Scholar 

  53. Arroyo JD, Jourdain AA, Calvo SE, Ballarano CA, Doench JG, Root DE, et al. A Genome-wide CRISPR Death Screen Identifies Genes Essential for Oxidative Phosphorylation. Cell Metab. 2016;24:875–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sheftel AD, Stehling O, Pierik AJ, Elsässer HP, Mühlenhoff U, Webert H, et al. Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis. Proc Natl Acad Sci USA. 2010;107:11775–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shi Y, Ghosh M, Kovtunovych G, Crooks DR, Rouault TA. Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis. Biochim Biophys Acta. 2012;1823:484–92.

    Article  CAS  PubMed  Google Scholar 

  56. Wikvall K. Hydroxylations in biosynthesis of bile acids. Isolation of a cytochrome P-450 from rabbit liver mitochondria catalyzing 26-hydroxylation of C27-steroids. J Biol Chem. 1984;259:3800–4.

    Article  CAS  PubMed  Google Scholar 

  57. Yoon PS, Rawlings J, Orme-Johnson WH, DeLuca HF. Renal mitochondrial ferredoxin active in 25-hydroxyvitamin D3 1 alpha-hydroxylase. Characterization of the iron-sulfur cluster using interprotein cluster transfer and electron paramagnetic resonance spectroscopy. Biochemistry. 1980;19:2172–6.

    Article  CAS  PubMed  Google Scholar 

  58. Chu J-W, Kimura T. Studies on Adrenal Steroid Hydroxylases: COMPLEX FORMATION OF THE HYDROXYLASE COMPONENTS. J Biol Chem. 1973;248:5183–7.

    Article  CAS  PubMed  Google Scholar 

  59. Hwang PM, Bunz F, Yu J, Rago C, Chan TA, Murphy MP, et al. Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nat Med. 2001;7:1111–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu G, Chen X. The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis. Oncogene. 2002;21:7195–204.

    Article  CAS  PubMed  Google Scholar 

  61. Mitani F, Ichiyama A. Enzymic studies on adrenocortical deoxycorticosterone 11beta-hydroxylase system. J Biol Chem. 1975;250:8010–5.

    Article  CAS  PubMed  Google Scholar 

  62. Drost J, Karthaus WR, Gao D, Driehuis E, Sawyers CL, Chen Y, et al. Organoid culture systems for prostate epithelial and cancer tissue. Nat Protoc. 2016;11:347–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fenor de la Maza MD, Chandran K, Rekowski J, Shui IM, Gurel B, Cross E, et al. Immune Biomarkers in Metastatic Castration-resistant Prostate Cancer. Eur Urol Oncol. 2022;5:659–67.

    Article  PubMed  Google Scholar 

  64. Nava Rodrigues D, Rescigno P, Liu D, Yuan W, Carreira S, Lambros MB, et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Investig. 2018;128:4441–53.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Sharp A, Coleman I, Yuan W, Sprenger C, Dolling D, Rodrigues DN, et al. Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer. J Clin Investig. 2019;129:192–208.

    Article  PubMed  Google Scholar 

  66. Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014;11:783–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank Lauren Zacharias, Hieu Vieu, Duyen Do, Jessica Sudderth, and the Children’s Research Institute Metabolomic core for their assistance with metabolic assays and analysis, as well as the Children’s Research Institute Flow Cytometry core and UTSW Live Cell Imaging core for providing training and equipment for microscopy and flow cytometry experiments. We also thank the Simmon’s Cancer Center’s Tissue Management Shared Resource, which provided the patient tissue reported in this publication with support from National Cancer Institute of the NIH award no. P30CA142543. Additionally, we would like to thank Jer-Tsong (JT) Hsieh, Donald Vander Griend, and Amina Zoubeidi for providing cell lines for this study. Additional thanks goes to Tracy Rosales for providing helpful information and advice on experiments involving glutaminase and glutamine metabolism. Some figures were created using biorender.com.

Funding

The National Cancer Institute at the National Institutes of Health Grant 1F31CA243276-01A1 and the Cancer Prevention and Research Institute of Texas Grant RP160157 (EBB). The National Cancer Institute at the National Institutes of Health Grant T32CA124334 (KP). Simmons Cancer Center at UT Southwestern for the Prostate Cancer Program, the Mimi and John Cole Prostate Cancer Fund, the Prostate Cancer Foundation, the Jasper L. and Jack Denton Wilson Foundation, and the Department of Defense Grants W81XWH-17-1-0674, W81XWH-19-1-0363, and W81XWH-21-1-0687 (GVR). RSM acknowledges funding support from National Cancer Institute (NCI)/NIH grant (R01CA245294), Cancer Prevention and Research Institute of Texas (CPRIT) Individual Investigator Research Award (RP190454), and US Department of Defense Breakthrough Award (W81XWH-21-1-0114).

Author information

Authors and Affiliations

  1. Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA

    Eliot B. Blatt, Karla Parra, Collin Gilbreath, Ram S. Mani & Ganesh V. Raj

  2. The Institute of Cancer Research, London, UK

    Antje Neeb, Lorenzo Buroni, Denisa Bogdan, Wei Yuan, Alec Paschalis, Suzanne Carreira & Johann S. de Bono

  3. Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA

    Yunpeng Gao & Ram S. Mani

  4. Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA

    Ralph J. DeBerardinis

  5. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA

    Ralph J. DeBerardinis

  6. Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK

    Johann S. de Bono

  7. Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA

    Ganesh V. Raj

  8. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA

    Ganesh V. Raj

Authors
  1. Eliot B. Blatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karla Parra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antje Neeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lorenzo Buroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Denisa Bogdan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yunpeng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Collin Gilbreath
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alec Paschalis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Suzanne Carreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ralph J. DeBerardinis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ram S. Mani
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Johann S. de Bono
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ganesh V. Raj
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Experiments were conceptualized, performed, and analyzed by EBB. EBB also responsible for methodology, funding acquisition, and writing the original and editing further manuscript drafts. Funding was acquired, experiments performed, and editing manuscript drafts by KP. Experiments performed and manuscript drafts edited by AN and LB. Formal analysis performed and manuscript drafts edited by YG, DB, and WY. Manuscript drafts edited by AP and SC. Experiments performed and manuscript drafts edited by CG. Methodology, supervision, and manuscript drafts edited by RJD. Supervision and manuscript drafts edited by RSM and JSdB. Funding acquisition, methodology, supervision, and manuscript drafts edited by GVR.

Corresponding author

Correspondence to Ganesh V. Raj.

Ethics declarations

Competing interests

GVR serves or has served in an advisory role to Bayer, Johnson and Johnson, Myovant, EtiraRx, Amgen, Pfizer and Astellas. He has or has had grant support from Bayer, EtiraRx and Johnson and Johnson. RJD is a founder and advisor for Atavistik Bioscience, and a scientific advisor for Agios Pharmaceuticals, Nirology Therapeutics, Droia Ventures, and Vida Ventures. JSdB has served on advisory boards and received fees from Amgen, Astra Zeneca, Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech/Roche, Genmab, GSK, Harpoon, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, and Vertex Pharmaceuticals; is an employee of the Institute of Cancer Research (ICR), which have received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and Vertex, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers, and PI3K/AKT pathway inhibitors (no personal income); was named as an inventor, with no financial interest for patent 8 822 438, submitted by Janssen that covers the use of abiraterone acetate with corticosteroids; has been the CI/PI of many industry-sponsored clinical trials; and is a National Institute for Health Research (NIHR) Senior Investigator. AN, LB, DB, WY, AP, SC, and JSdB are employees of the Institute of Cancer Research (ICR), which has commercial interest in abiraterone. No other authors have any potential conflicts of interest to disclose.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blatt, E.B., Parra, K., Neeb, A. et al. Critical role of antioxidant programs in enzalutamide-resistant prostate cancer. Oncogene 42, 2347–2359 (2023). https://doi.org/10.1038/s41388-023-02756-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02756-w

This article is cited by

Search

Advanced search

Quick links