期刊
CANCER CELL
卷 35, 期 3, 页码 385-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2019.01.018
关键词
-
资金
- NIH [R01CA192642, R01CA218254, R01DK108743, R01CA211794, R01CA207177]
- La Caixa'' fellowship [LCF/BQ/AN15/10380036]
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)lambda/l 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 supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKC lambda/l deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.
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