Title | Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Reina-Campos M, Linares JF, Duran A, Cordes T, L'Hermitte A, Badur MG, Bhangoo MS, Thorson PK, Richards A, Rooslid T, Garcia-Olmo DC, Nam-Cha SY, Salinas-Sanchez AS, Eng K, Beltran H, Scott DA, Metallo CM, Moscat J, Diaz-Meco MT |
Journal | Cancer Cell |
Volume | 35 |
Issue | 3 |
Pagination | 385-400.e9 |
Date Published | 2019 03 18 |
ISSN | 1878-3686 |
Keywords | Activating Transcription Factor 4, Biosynthetic Pathways, Carcinoma, Neuroendocrine, Cell Line, Tumor, DNA Methylation, Down-Regulation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Humans, Isoenzymes, Male, Mechanistic Target of Rapamycin Complex 1, Prostatic Neoplasms, Protein Kinase C, S-Adenosylmethionine, Serine |
Abstract | 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. |
DOI | 10.1016/j.ccell.2019.01.018 |
Alternate Journal | Cancer Cell |
PubMed ID | 30827887 |
PubMed Central ID | PMC6424636 |
Grant List | R01 DK108743 / DK / NIDDK NIH HHS / United States R01 CA211794 / CA / NCI NIH HHS / United States R01 CA207177 / CA / NCI NIH HHS / United States R01 CA192642 / CA / NCI NIH HHS / United States R01 CA218254 / CA / NCI NIH HHS / United States |
Related Faculty:
Juan Francisco Linares Rodriguez, Ph.D. Maria Diaz-Meco Conde, Ph.D.