TitleInterplay between hypoxia and androgen controls a metabolic switch conferring resistance to androgen/AR-targeted therapy.
Publication TypeJournal Article
Year of Publication2018
AuthorsGeng H, Xue C, Mendonca J, Sun X-X, Liu Q, Reardon PN, Chen Y, Qian K, Hua V, Chen A, Pan F, Yuan J, Dang S, Beer TM, Dai M-S, Kachhap SK, Qian DZ
JournalNat Commun
Date Published2018 11 26
KeywordsAndrogens, Cell Line, Tumor, Drug Resistance, Neoplasm, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Glucose, Glucose-6-Phosphate Isomerase, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Male, Molecular Targeted Therapy, Phenylthiohydantoin, Prostatic Neoplasms, Receptors, Androgen, Transcription, Genetic, Tumor Hypoxia, Up-Regulation

Despite recent advances, the efficacy of androgen/androgen receptor (AR)-targeted therapy remains  limited for many patients with metastatic prostate cancer. This is in part because prostate cancers adaptively switch to the androgen/AR-independent pathway for survival and growth, thereby conferring therapy resistance. Tumor hypoxia is considered as a major cause of treatment resistance. However, the exact mechanism is largely unclear. Here we report that chronic-androgen deprivation therapy (ADT) in the condition of hypoxia induces adaptive androgen/AR-independence, and therefore confers resistance to androgen/AR-targeted therapy, e.g., enzalutamide. Mechanistically, this is mediated by glucose-6-phosphate isomerase (GPI), which is transcriptionally repressed by AR in hypoxia, but restored and increased by AR inhibition. In turn, GPI maintains glucose metabolism and energy homeostasis in hypoxia by redirecting the glucose flux from androgen/AR-dependent pentose phosphate pathway (PPP) to hypoxia-induced glycolysis pathway, thereby reducing the growth inhibitory effect of enzalutamide. Inhibiting GPI overcomes the therapy resistance in hypoxia in vitro and increases enzalutamide efficacy in vivo.

Alternate JournalNat Commun
PubMed ID30478344
PubMed Central IDPMC6255907
Grant ListR01 CA186241 / CA / NCI NIH HHS / United States
R01 CA207377 / CA / NCI NIH HHS / United States