Drug resistance to the androgen receptor (AR) antagonist is a critical obstacle in the clinic for advanced prostate cancers. Especially, AR antagonist treatment-induced neuroendocrine progression represents a lethal and therapy-resistant subtype. Although transcriptional and epigenetic lineage plasticity have been extensively implicated in treatment-induced neuroendocrine progression, the contribution of metabolic adaptation remains incompletely understood. Here, we identified a previously unrecognized metabolic reprogramming mechanism induced by AR antagonists in castration-resistant prostate cancer (CRPC) models. AR antagonist treatment markedly enhanced glycolytic activity and induced glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Genetic depletion of GAPDH suppressed AR antagonist-induced glycolytic activation, altered transcriptomic and metabolic programs, reduced neuroendocrine-associated marker expression, and inhibited xenograft tumor growth. Mechanistically, GAPDH promoter pulldown coupled with mass spectrometry, siRNA screening, and chromatin immunoprecipitation assays identified myeloid zinc finger-1 (MZF1) as a key transcription factor for Enzalutamide-induced GAPDH gene expression. Pharmacological inhibition of GAPDH using koningic acid (KA) or penta-O-galloyl-{beta}-D-glucopyranose (PGG) significantly suppressed tumor growth and attenuated neuroendocrine-associated molecular programs in CRPC cell-derived xenograft and patient-derived t-NEPC xenograft models. Collectively, our findings identify an AR antagonist-induced MZF1-GAPDH signaling axis that promotes glycolytic activation and neuroendocrine-associated metabolic adaptation during treatment resistance. These results support targeting GAPDH-dependent metabolic reprogramming as a potential therapeutic strategy for treatment-resistant prostate cancer.
Liu, W., He, L., Zhong, C., Wang, Y., zhang, d., Mirza, M., Li, B.
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