[PDF][PDF] Increased serine and one-carbon pathway metabolism by PKCλ/ι deficiency promotes neuroendocrine prostate cancer
Cancer Cell, 2019•cell.com
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) λ/ι 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 …
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) λ/ι 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 …
Summary
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)λ/ι 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 PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.
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