Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer

Cancer Cell. 2019 Mar 18;35(3):385-400.e9. doi: 10.1016/j.ccell.2019.01.018. Epub 2019 Feb 28.


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.

Keywords: ATF4; PKClambda; aPKC; cancer metabolism; epigenetics; lineage plasticity; mTOR; neuroendocrine; prostate cancer; serine metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Biosynthetic Pathways
  • Carcinoma, Neuroendocrine / genetics
  • Carcinoma, Neuroendocrine / metabolism
  • Carcinoma, Neuroendocrine / pathology*
  • Cell Line, Tumor
  • DNA Methylation
  • Down-Regulation*
  • Epigenesis, Genetic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Isoenzymes / deficiency*
  • Male
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Protein Kinase C / deficiency*
  • S-Adenosylmethionine / metabolism
  • Serine / metabolism*


  • ATF4 protein, human
  • Isoenzymes
  • Activating Transcription Factor 4
  • Serine
  • S-Adenosylmethionine
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Kinase C
  • protein kinase C lambda