ArticleEMBO molecular medicine2021
Androgen receptor (AR) antagonism triggers acute succinate-mediated adaptive responses to reactivate AR signaling.
Article in EMBO molecular medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
- Recent Advances in Androgen Receptor Pathway Inhibitors for Castration-Sensitive Prostate Cancer.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Baicalin mitigates polycystic ovary syndrome‑associated non‑alcoholic fatty liver disease by inhibiting the AR/SREBP1 axis.International journal of molecular medicine · 2025Article
- The Role of HINT3 in Myocardial Ischemia-Reperfusion Injury in Male Mice: Mechanisms Involving SDHA and its Acetylation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies.Cell communication and signaling : CCS · 2024Review
- Article
- SGC-CAMKK2-1: A Chemical Probe for CAMKK2.Cells · 2023Article
- Regulation and role of CAMKK2 in prostate cancer.Nature reviews. Urology · 2022Review
- Ivermectin induces cell cycle arrest and caspase-dependent apoptosis in human urothelial carcinoma cells.International journal of medical sciences · 2022Article
- Androgen receptor (AR) antagonism triggers acute succinate-mediated adaptive responses to reactivate AR signaling.EMBO molecular medicine · 2021Article
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.