Increased Serine and One-Carbon Pathway Metabolism by PKC
Menée in vitro, à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un cancer de la prostate et à l'aide de xénogreffes sur un modèle murin, cette étude démontre que la perte de l'expression de la protéine kinase C lambda/iota dans les cellules cancéreuses favorise le développement d'une tumeur neuro-endocrine en augmentant la biosynthèse de la sérine et le métabolisme des radicaux monocarbonés
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)?/? 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?/? deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.
Cancer Cell 2019