دورية أكاديمية
Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer.
العنوان: | Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer. |
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المؤلفون: | Alizadeh-Ghodsi M; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.; Freemasons Centre for Male Health and Wellbeing, The University of Adelaide, Adelaide, SA, Australia., Owen KL; Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Townley SL; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia.; Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, SA, Australia., Zanker D; Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Rollin SPG; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia.; Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, SA, Australia., Hanson AR; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia.; Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, SA, Australia., Shrestha R; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.; Freemasons Centre for Male Health and Wellbeing, The University of Adelaide, Adelaide, SA, Australia.; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia., Toubia J; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.; ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology and University of South Australia, Frome Road, Adelaide, SA, Australia., Gargett T; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia., Chernukhin I; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom., Luu J; Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Cowley KJ; Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Clark A; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia., Carroll JS; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom., Simpson KJ; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.; Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Winter JM; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia., Lawrence MG; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.; Cabrini Institute, Malvern, Victoria, Australia.; Melbourne Urological Research Alliance (MURAL), Monash Biomedicine Discovery Institute Cancer Program, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia., Butler LM; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia., Risbridger GP; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.; Cabrini Institute, Malvern, Victoria, Australia.; Melbourne Urological Research Alliance (MURAL), Monash Biomedicine Discovery Institute Cancer Program, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia., Thierry B; ARC Centre of Excellence in Convergent Bio and Nano Science and Technology, University of South Australia, Frome Road, Adelaide, SA, Australia.; Future Industries Institute, University of South Australia, Mawson Lakes, SA, Australia., Taylor RA; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.; Cabrini Institute, Malvern, Victoria, Australia.; Melbourne Urological Research Alliance (MURAL), Monash Biomedicine Discovery Institute Cancer Program, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.; Monash Partners Comprehensive Cancer Consortium, Monash Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Physiology, Monash University, Clayton, Victoria, Australia., Hickey TE; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia., Parker BS; Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Tilley WD; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.; Freemasons Centre for Male Health and Wellbeing, The University of Adelaide, Adelaide, SA, Australia., Selth LA; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA, Australia.; Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, SA, Australia. |
المصدر: | Cancer research communications [Cancer Res Commun] 2022 Jul 25; Vol. 2 (7), pp. 706-724. Date of Electronic Publication: 2022 Jul 25 (Print Publication: 2022). |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 9918281580506676 Publication Model: eCollection Cited Medium: Internet ISSN: 2767-9764 (Electronic) Linking ISSN: 27679764 NLM ISO Abbreviation: Cancer Res Commun |
أسماء مطبوعة: | Original Publication: [Philadelphia, Pennsylvania] : American Association for Cancer Research, [2021]- |
مواضيع طبية MeSH: | Receptors, Androgen*/genetics , Prostatic Neoplasms*/drug therapy, Male ; Humans ; Animals ; Mice ; Androgens/pharmacology ; Androgen Antagonists/pharmacology ; CD8-Positive T-Lymphocytes/metabolism ; DNA |
مستخلص: | Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer. Paradoxically, activation of AR can also inhibit the growth of prostate cancer in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of prostate cancer cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in prostate cancer cells. MeT potently downregulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, including upregulation of endogenous retrovirus (ERV) transcripts after sustained MeT treatment. Increased ERV expression led to accumulation of double-stranded RNA and a "viral mimicry" response characterized by activation of IFN signaling, upregulation of MHC class I molecules, and enhanced recognition of murine prostate cancer cells by CD8 + T cells. Positive associations between AR activity and ERVs/antiviral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of prostate cancer cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies. Significance: Our study demonstrates that potent androgen stimulation of prostate cancer cells can elicit a viral mimicry response, resulting in enhanced IFN signaling. This finding may have implications for the development of strategies to sensitize prostate cancer to immunotherapies. Competing Interests: S.P.G. Rollin reports personal fees from Flinders Foundation during the conduct of the study. J.M. Winter reports non-financial support from The University of Adelaide and Flinders University of South Australia during the conduct of the study. M.G. Lawrence reports non-financial support from Pfizer, Astellas, and Zenith Epigenetics outside the submitted work. L.M. Butler reports grants from Cancer Council of South Australia during the conduct of the study. G.P. Risbridger reports non-financial support from Pfizer, Astellas, and Zenith Epigenetics outside the submitted work. R.A. Taylor reports non-financial support from Pfizer, Astellas, and Zenith Epigenetics outside the submitted work. T.E. Hickey reports grants from National Health and Medical Research Council (Australia), National Breast Cancer Foundation (Australia), and Movember (Australia) during the conduct of the study. B.S. Parker reports grants from The University of Melbourne during the conduct of the study; grants from National Health and Medical Research Council and National Breast Cancer Foundation outside the submitted work. L.A. Selth reports grants from The Hospital Research Foundation, Cancer Council of South Australia, Movember Foundation and the Prostate Cancer Foundation of Australia, Cancer Council of South Australia, National Breast Cancer Foundation, Australian Government, Victorian Cancer Agency, Movember Foundation, Movember Foundation and National Breast Cancer Foundation, and National Health and Medical Research Council of Australia during the conduct of the study. No disclosures were reported by the other authors. (© 2022 The Authors; Published by the American Association for Cancer Research.) |
References: | Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-18. (PMID: 32343604) Drug Metab Dispos. 2003 Sep;31(9):1117-24. (PMID: 12920167) Prostate. 1993;23(3):213-23. (PMID: 7694266) Cancer Cell. 2019 May 13;35(5):782-797.e8. (PMID: 31085178) Front Microbiol. 2018 Feb 13;9:178. (PMID: 29487579) Cell. 2018 Jul 26;174(3):549-563.e19. (PMID: 29937226) Cell. 2015 May 21;161(5):1215-1228. (PMID: 26000489) Cancer. 1964 Jan;17:95-9. (PMID: 14102076) Oncotarget. 2013 May;4(5):691-704. (PMID: 23674566) Eur J Cancer. 2021 Feb;144:302-309. (PMID: 33383350) Cell Rep. 2016 Oct 18;17(4):966-976. (PMID: 27760327) Lancet Oncol. 2018 Jan;19(1):76-86. (PMID: 29248236) Cell Rep. 2021 Jan 5;34(1):108585. (PMID: 33406413) Bioinformatics. 2014 Apr 1;30(7):923-30. (PMID: 24227677) Nat Med. 2012 Aug;18(8):1224-31. (PMID: 22820642) Endocrinology. 1984 Jun;114(6):2100-6. (PMID: 6539197) Eur Urol. 2017 Mar;71(3):499. (PMID: 27692705) Methods. 2007 Aug;42(4):377-87. (PMID: 17560325) Cancer Res. 2006 Aug 1;66(15):7490-501. (PMID: 16885346) Nat Commun. 2019 Nov 19;10(1):5228. (PMID: 31745090) Nucleic Acids Res. 2016 Jul 8;44(W1):W160-5. (PMID: 27079975) J Interferon Cytokine Res. 2013 Apr;33(4):162-70. (PMID: 23570382) Am Fam Physician. 2017 Oct 1;96(7):441-449. (PMID: 29094914) Nat Biotechnol. 2008 Nov;26(11):1293-300. (PMID: 18978777) Ther Adv Med Oncol. 2018 Aug 29;10:1758835918793105. (PMID: 30181782) Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17492-7. (PMID: 24101480) Nucleic Acids Res. 2019 Jul 2;47(W1):W199-W205. (PMID: 31114916) J Clin Invest. 2019 Jul 16;129(10):4245-4260. (PMID: 31310591) Clin Cancer Res. 2011 Jun 15;17(12):3858-64. (PMID: 21385925) Cancers (Basel). 2017 Dec 06;9(12):. (PMID: 29210989) Cancer Res. 2018 Aug 15;78(16):4716-4730. (PMID: 29921690) Cell. 2015 Jan 15;160(1-2):48-61. (PMID: 25594174) Methods Mol Biol. 2016;1418:391-416. (PMID: 27008025) Nucleic Acids Res. 2003 Jun 15;31(12):3101-13. (PMID: 12799438) Eur Urol. 2020 Feb;77(2):144-155. (PMID: 31227306) JCI Insight. 2019 Oct 3;4(19):. (PMID: 31503550) Endocrinology. 2006 Jun;147(6):3016-26. (PMID: 16497801) Nature. 2007 May 24;447(7143):425-32. (PMID: 17522676) Oncogene. 2005 Jan 6;24(1):199-211. (PMID: 15637593) J Steroid Biochem Mol Biol. 1994 Aug;50(3-4):151-9. (PMID: 7519439) Sci Transl Med. 2015 Jan 7;7(269):269ra2. (PMID: 25568070) BMC Genomics. 2014 Jul 11;15:583. (PMID: 25012247) Cancer Res. 1965 Aug;25(7):1163-7. (PMID: 5897831) PLoS Pathog. 2018 Aug 16;14(8):e1007148. (PMID: 30114241) Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):E10981-E10990. (PMID: 29203668) Mol Endocrinol. 1998 Jul;12(7):941-53. (PMID: 9658399) Nucleic Acids Res. 2015 Jul 1;43(W1):W566-70. (PMID: 25969447) Cancer Res. 2005 May 1;65(9):3624-32. (PMID: 15867357) Cell Syst. 2015 Dec 23;1(6):417-425. (PMID: 26771021) Br J Pharmacol. 2008 Jun;154(3):502-21. (PMID: 18500378) Chem Res Toxicol. 2003 Oct;16(10):1338-58. (PMID: 14565775) Mol Cancer Res. 2003 Mar;1(5):385-92. (PMID: 12651911) Bioinformatics. 2010 Jan 1;26(1):139-40. (PMID: 19910308) Cancer Discov. 2013 Nov;3(11):1245-53. (PMID: 24027196) Eur Urol. 2021 May;79(5):692-699. (PMID: 32624280) Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517) Nature. 2009 Nov 5;462(7269):108-12. (PMID: 19847166) Steroids. 2016 Jan;105:68-95. (PMID: 26639430) Cell. 2017 Nov 30;171(6):1284-1300.e21. (PMID: 29195073) Oncotarget. 2016 Aug 16;7(33):52810-52817. (PMID: 27429197) Epigenetics. 2010 Feb 16;5(2):100-4. (PMID: 20160483) Mol Cell. 2010 May 28;38(4):576-89. (PMID: 20513432) EMBO Rep. 2020 Jun 4;21(6):e50162. (PMID: 32314873) Eur Urol. 2018 Nov;74(5):562-572. (PMID: 30049486) Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886) Br J Cancer. 1991 Jul;64(1):47-53. (PMID: 1713053) Elife. 2017 Aug 18;6:. (PMID: 28826481) Nature. 2017 Aug 24;548(7668):471-475. (PMID: 28813415) Oncol Rep. 2014 Jan;31(1):34-40. (PMID: 24173286) Cell. 2015 Aug 27;162(5):961-73. (PMID: 26317465) J Clin Endocrinol Metab. 2004 May;89(5):2207-13. (PMID: 15126543) Liver Int. 2008 Feb;28(2):278-82. (PMID: 17900246) Horm Res Paediatr. 2010;74(4):292-6. (PMID: 20938205) Immunity. 2006 May;24(5):633-42. (PMID: 16713980) Endocr Relat Cancer. 2012 Jul 22;19(4):599-613. (PMID: 22719059) Nucleic Acids Res. 2015 Jul 13;43(12):5880-97. (PMID: 25908785) Arch Toxicol. 2011 Apr;85(4):285-92. (PMID: 20924560) Transl Androl Urol. 2020 Mar;9(Suppl 2):S135-S148. (PMID: 32257854) Oncogene. 2000 Feb 3;19(5):670-9. (PMID: 10698512) Cancer Discov. 2017 Jan;7(1):54-71. (PMID: 27784708) J Clin Oncol. 2021 Apr 20;39(12):1371-1382. (PMID: 33617303) Cell. 2015 Nov 5;163(4):1011-25. (PMID: 26544944) Prostate. 2020 Apr;80(5):407-411. (PMID: 31972048) Sci Signal. 2013 Apr 02;6(269):pl1. (PMID: 23550210) N Engl J Med. 2010 Jul 29;363(5):411-22. (PMID: 20818862) Nat Commun. 2021 Aug 19;12(1):5049. (PMID: 34413304) Nat Cancer. 2021 Apr;2(4):444-456. (PMID: 33899001) Cancer Res. 2017 Jul 1;77(13):3417-3430. (PMID: 28473532) J Clin Invest. 2021 Jun 15;131(12):. (PMID: 34128479) Bioinformatics. 2010 Mar 15;26(6):841-2. (PMID: 20110278) Annu Rev Med. 2020 Jan 27;71:33-45. (PMID: 31613683) Endocr Relat Cancer. 2016 Dec;23(12):T179-T197. (PMID: 27799360) Nat Methods. 2012 Jul;9(7):671-5. (PMID: 22930834) Brief Bioinform. 2013 Mar;14(2):178-92. (PMID: 22517427) Transl Androl Urol. 2013 Sep 1;2(3):148-157. (PMID: 25580383) Cell. 2015 Aug 27;162(5):974-86. (PMID: 26317466) Nat Rev Immunol. 2020 Sep;20(9):537-551. (PMID: 32203325) |
معلومات مُعتمدة: | 20411 United Kingdom CRUK_ Cancer Research UK |
المشرفين على المادة: | 0 (Receptors, Androgen) 0 (Androgens) 0 (Androgen Antagonists) 9007-49-2 (DNA) |
تواريخ الأحداث: | Date Created: 20230316 Date Completed: 20230728 Latest Revision: 20240306 |
رمز التحديث: | 20240306 |
مُعرف محوري في PubMed: | PMC10010308 |
DOI: | 10.1158/2767-9764.CRC-21-0139 |
PMID: | 36923279 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2767-9764 |
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DOI: | 10.1158/2767-9764.CRC-21-0139 |