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 metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well known tumour-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/

SUBMITTER: Dr. Neetu Saxena 

PROVIDER: S-SCDT-EMM-2020-13427 | biostudies-other |

REPOSITORIES: biostudies-other