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

Miguel Reina-Campos; Juan F Linares; Angeles Duran; Thekla Cordes; Antoine L'Hermitte; Mehmet G Badur; Munveer S Bhangoo; Phataraporn K Thorson; Alicia Richards; Tarmo Rooslid; Dolores C Garcia-Olmo; Syongh Y Nam-Cha; Antonio S Salinas-Sanchez; Ken Eng; Himisha Beltran; David A Scott; Christian M Metallo; Jorge Moscat; Maria T Diaz-Meco

doi:10.1016/j.ccell.2019.01.018

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.

Authors

Miguel Reina-Campos¹, Juan F Linares², Angeles Duran², Thekla Cordes³, Antoine L'Hermitte², Mehmet G Badur³, Munveer S Bhangoo⁴, Phataraporn K Thorson⁵, Alicia Richards⁶, Tarmo Rooslid⁷, Dolores C Garcia-Olmo⁸, Syongh Y Nam-Cha⁹, Antonio S Salinas-Sanchez¹⁰, Ken Eng¹¹, Himisha Beltran¹², David A Scott¹³, Christian M Metallo³, Jorge Moscat², Maria T Diaz-Meco¹⁴

Affiliations

¹ Cancer 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.
² Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
³ Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Division of Hematology-Oncology Scripps Clinic, 10666 N. Torrey Pines Road, La Jolla, CA 92037, USA.
⁵ Depatment of Pathology, Scripps Clinic Medical Group, 10666 Torrey Pines Road, La Jolla, CA 92037, USA.
⁶ Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
⁷ Conrad Prebys Center for Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
⁸ Centre de Recerca Experimental Biomèdica Aplicada (CREBA), IRBLLEIDA, 25138 Lleida, Spain.
⁹ Pathology Department, Director of the Research Unit Biobank, University of Castilla-La Mancha, School of Medicine, 02006 Albacete, Spain.
¹⁰ Urology Department, Research Unit, University Hospital Complex of Albacete, School of Medicine, 02006 Albacete, Spain.
¹¹ Department of Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
¹² Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
¹³ Cancer Metabolism Core, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
¹⁴ Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: mdmeco@sbpdiscovery.org.

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.

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*

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding