GSE109758
Increased Serine and One Carbon Pathway Metabolism by PKCl/i Deficiency Promotes Neuroendocrine Prostate Cancer [MeDIP-Seq]
Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)l/i is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming increases intracellular SAM levels to support cell proliferation and epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCl/i deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa. Overall design: sgC (WT) and PKCl/i KO (sgPKCl/i) C42B cells were profiled under normal conditions.