دورية أكاديمية
أعرض في EDS

Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer.

التفاصيل البيبلوغرافية
العنوان: Potent Stimulation of the Androgen Receptor Instigates a Viral Mimicry Response in Prostate Cancer.
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.)
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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
الوصف
تدمد:2767-9764
DOI:10.1158/2767-9764.CRC-21-0139