Androgen receptor (AR) antagonism triggers acute succinate‐mediated adaptive responses to reactivate AR signaling

Androgen receptor (AR) antagonism triggers acute succinate‐mediated adaptive responses to reactivate AR signaling

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 metabol...

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Main Authors: Neetu Saxena, Eliana Beraldi, Ladan Fazli, Syam Prakash Somasekharan, Hans Adomat, Fan Zhang, Chidi Molokwu, Anna Gleave, Lucia Nappi, Kimberly Nguyen, Pavn Brar, Nicholas Nikesitch, Yuzhuo Wang, Colin Collins, Poul H Sorensen, Martin Gleave
Format: Article
Language:English
Published: Springer Nature 2021-03-01
Series:EMBO Molecular Medicine
Subjects:
Androgen receptor
Hsp27
prostate cancer
succinate dehydrogenase
succinate
Online Access:https://doi.org/10.15252/emmm.202013427
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Summary: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.
ISSN:1757-4676
1757-4684

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