Androgen receptor (AR) antagonism triggers acute succinate‐mediated adaptive responses to reactivate AR signaling. Issue 5 (11th March 2021)

• Record Type: Journal Article
• Authors: Saxena, Neetu; Beraldi, Eliana; Fazli, Ladan; Somasekharan, Syam Prakash; Adomat, Hans; Zhang, Fan; Molokwu, Chidi; Gleave, Anna; Nappi, Lucia; Nguyen, Kimberly; Brar, Pavn; Nikesitch, Nicholas; Wang, Yuzhuo; Collins, Colin; Sorensen, Poul H; Gleave, Martin
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 5(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-11
• Subjects: Androgen receptor -- Hsp27 -- prostate cancer -- succinate dehydrogenase -- succinate; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202013427
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Treatment‐induced adaptive pathways converge to support androgen receptor (AR) reactivation and emergence of castration‐resistant prostate cancer (PCa) after AR pathway inhibition (ARPI). We set out to explore poorly defined acute adaptive responses that orchestrate shifts in energy metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well‐known tumor suppressor activity. We show that AR directly regulates transcription of its catalytic subunits (SDHA, SDHB) via androgen response elements (AREs). ARPI acutely suppresses SDH activity, leading to accumulation of the oncometabolite, succinate. Succinate triggers calcium ions release from intracellular stores, which in turn phospho‐activates the AR‐cochaperone, Hsp27 via p‐CaMKK2/p‐AMPK/p‐p38 axis to enhance AR protein stabilization and activity. Activation of this pathway was seen in tissue microarray analysis on prostatectomy tissues and patient‐derived xenografts. This adaptive response is blocked by co‐targeting AR with Hsp27 under both in vitro and in vivo studies, sensitizing PCa cells to ARPI treatments. Synopsis: Prostate cancer becomes resistant to treatments targeting oncogenic androgen receptor (AR) via coordinated activity of multiple adaptive responses. This study defines metabolic reprogramming in response to AR pathway inhibition (ARPI) that supports AR reactivation. AR regulatory elements (AREs) were identified in catalytic subunits SDHA and SDHB of succinate dehydrogenase (SDH) enzyme. ARPI inhibited SDH activity resulting in accumulation of intracellular succinate. Intracellular succinate triggered Ca 2+ release to activate p‐CAMKK2/p‐AMPK/p‐p38 axis, increasing levels of the AR co‐chaperone p‐Hsp27 to support AR protein and signaling. Co‐targeting p‐Hsp27 with ARPI abrogated this succinate‐mediated adaptive loop and enhanced prostate cancer sensitivity to ARPI. Abstract : Prostate cancer becomes resistant to treatments targeting oncogenic androgen receptor (AR) via coordinated activity of multiple adaptive responses. This study defines metabolic reprogramming in response to AR pathway inhibition (ARPI) that supports AR reactivation.