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

Miguel Reina-Campos1, Juan F Linares2, Angeles Duran2

  • 1Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA; Sanford Burnham Prebys Graduate School of Biomedical Sciences, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Cancer Cell
|March 5, 2019
PubMed

Insights

Protein kinase C (PKC)λ/ι deficiency drives neuroendocrine prostate cancer (NEPC) by upregulating serine biosynthesis. This metabolic shift fuels NEPC progression and offers potential therapeutic targets for castration-resistant prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Androgen receptor-targeted therapies increase neuroendocrine prostate cancer (NEPC), a lethal subtype of castration-resistant prostate cancer (PCa).
  • Currently, no effective therapies exist for NEPC.
  • Understanding NEPC's underlying mechanisms is crucial for developing new treatments.

Purpose of the Study:

  • To investigate the role of protein kinase C (PKC)λ/ι in the development of NEPC.
  • To identify metabolic alterations associated with NEPC.
  • To uncover potential therapeutic targets for NEPC.

Main Methods:

  • Analysis of PKCλ/ι expression in de novo and therapy-induced NEPC models.
  • Investigation of serine biosynthesis pathways.
  • Assessment of the mTORC1/ATF4 signaling pathway.
  • Measurement of intracellular S-adenosyl methionine (SAM) levels.
  • Evaluation of epigenetic modifications.

Main Results:

  • PKCλ/ι is downregulated in NEPC.
  • PKCλ/ι deficiency upregulates serine biosynthesis via an mTORC1/ATF4-dependent pathway.
  • Metabolic reprogramming enhances cancer cell proliferation.
  • Increased intracellular SAM levels promote epigenetic changes characteristic of NEPC.

Conclusions:

  • PKCλ/ι deficiency represents a key metabolic vulnerability in NEPC.
  • Targeting the PKCλ/ι-mediated metabolic pathway may offer a strategy to prevent therapy resistance in prostate cancer.
  • This study identifies novel therapeutic targets for NEPC.
Keywords:
ATF4PKClambdaaPKCcancer metabolismepigeneticslineage plasticitymTORneuroendocrineprostate cancerserine metabolism

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