The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis
Charles E. Massie,Andy G. Lynch,Antonio Ramos-Montoya,Joan Boren,Rory Stark,Ladan Fazli,Anne Y. Warren,H Scott,Basetti Madhu,N L Sharma,Helene Bon,Vinny Zecchini,D. Smith,Gina M. DeNicola,Nik Mathews,Michelle Osborne,James Hadfield,Stewart MacArthur,Boris Adryan,Scott K. Lyons,Kevin M. Brindle,John R. Griffiths,Martin E. Gleave,Paul S. Rennie,David E. Neal,Ian G. Mills +25 more
TLDR
Cal calcium/calmodulin‐dependent protein kinase kinase 2 is highlighted, which it is shown is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone‐dependent modulator of anabolic metabolism.Abstract:
The androgen receptor (AR) is a key regulator of prostate growth and the principal drug target for the treatment of prostate cancer. Previous studies have mapped AR targets and identified some candidates which may contribute to cancer progression, but did not characterize AR biology in an integrated manner. In this study, we took an interdisciplinary approach, integrating detailed genomic studies with metabolomic profiling and identify an anabolic transcriptional network involving AR as the core regulator. Restricting flux through anabolic pathways is an attractive approach to deprive tumours of the building blocks needed to sustain tumour growth. Therefore, we searched for targets of the AR that may contribute to these anabolic processes and could be amenable to therapeutic intervention by virtue of differential expression in prostate tumours. This highlighted calcium/calmodulin-dependent protein kinase kinase 2, which we show is overexpressed in prostate cancer and regulates cancer cell growth via its unexpected role as a hormone-dependent modulator of anabolic metabolism. In conclusion, it is possible to progress from transcriptional studies to a promising therapeutic target by taking an unbiased interdisciplinary approach.read more
Citations
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Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches
TL;DR: The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.
Journal ArticleDOI
Androgen insensitivity syndrome
Ieuan A. Hughes,John D. Davies,Trevor Bunch,Vickie Pasterski,Kiki Mastroyannopoulou,Jane MacDougall +5 more
TL;DR: Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.
Evidence for an Alternative Glycolytic Pathway in Rapidly Proliferating Cells
Matthew G. Vander Heiden,Matthew G. Vander Heiden,Jason W. Locasale,Jason W. Locasale,Kenneth D. Swanson,Hadar Sharfi,Gregory J. Heffron,Daniel Amador-Noguez,Heather R. Christofk,Gerhard Wagner,Joshua D. Rabinowitz,John M. Asara,Lewis C. Cantley,Lewis C. Cantley +13 more
TL;DR: In this paper, the authors demonstrate that phosphoenolpyruvate (PEP) can act as a phosphate donor in mammalian cells because PEP participates in the phosphorylation of the glycolytic enzyme phosphoglycerate mutase (PGAM1) in PKM2-expressing cells.
Journal ArticleDOI
Genomic hallmarks of localized, non-indolent prostate cancer
Michael Fraser,Veronica Y. Sabelnykova,Takafumi N. Yamaguchi,Lawrence E. Heisler,Julie Livingstone,Vincent Huang,Yu Jia Shiah,Fouad Yousif,Xihui Lin,Andre P. Masella,Natalie S. Fox,Natalie S. Fox,Michael Xie,Stephenie D. Prokopec,Alejandro Berlin,Emilie Lalonde,Emilie Lalonde,Musaddeque Ahmed,Dominique Trudel,Xuemei Luo,Timothy Beck,Alice Meng,Junyan Zhang,Alister D'Costa,Robert E. Denroche,Haiying Kong,Shadrielle Melijah G. Espiritu,Melvin L.K. Chua,Ada Wong,Taryne Chong,Michelle Sam,Jeremy Johns,Lee Timms,Nicholas Buchner,Michèle Orain,Valérie Picard,Hélène Hovington,Alexander Murison,Ken Kron,Nicholas J. Harding,Christine P'ng,Kathleen E. Houlahan,Kenneth C. Chu,Bryan Lo,Francis Nguyen,Constance H. Li,Constance H. Li,Ren X. Sun,Ren X. Sun,Richard de Borja,Christopher I Cooper,Julia F. Hopkins,Shaylan K. Govind,Clement Fung,Daryl Waggott,Jeffrey Green,Syed Haider,Michelle Chan-Seng-Yue,Esther Jung,Zhiyuan Wang,Alain Bergeron,Alan Dal Pra,Louis Lacombe,Colin Collins,Colin Collins,Cenk Sahinalp,Mathieu Lupien,Mathieu Lupien,Neil E. Fleshner,Housheng Hansen He,Housheng Hansen He,Yves Fradet,Bernard Têtu,Theodorus van der Kwast,John Douglas Mcpherson,John Douglas Mcpherson,Robert G. Bristow,Robert G. Bristow,Paul C. Boutros,Paul C. Boutros +79 more
TL;DR: It is suggested that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates and numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberration outperformed well-described prognostic biomarkers.
Journal ArticleDOI
Genetics and biology of prostate cancer.
TL;DR: Improved disease management will also benefit from artificial intelligence-based expert decision support systems for proper standard of care, prognostic determinant biomarkers to minimize overtreatment of localized disease, and new standards of care accelerated by next-generation adaptive clinical trials.
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