Format

Send to

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

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

Author information

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

PMID:
30827887
PMCID:
PMC6424636
[Available on 2020-03-18]
DOI:
10.1016/j.ccell.2019.01.018

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center