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

Activating Transcription Factor 4 / metabolism Biosynthetic Pathways Carcinoma, Neuroendocrine / genetics 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 Protein Kinase C / deficiency S-Adenosylmethionine / metabolism Serine / metabolism
ATF4 PKClambda aPKC cancer metabolism epigenetics lineage plasticity mTOR neuroendocrine prostate cancer serine metabolism

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
18 03 2019
Historique:
received: 25 05 2018
revised: 13 11 2018
accepted: 28 01 2019
pubmed: 5 3 2019
medline: 24 12 2019
entrez: 5 3 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ccell.2019.01.018 PMID: 30827887 PMC: PMC6424636
pubmed: 30827887
pii: S1535-6108(19)30052-2
doi: 10.1016/j.ccell.2019.01.018
pmc: PMC6424636
mid: NIHMS1520448
pii:
doi:

Substances chimiques

ATF4 protein, human 0
Isoenzymes 0
Activating Transcription Factor 4 145891-90-3
Serine 452VLY9402
S-Adenosylmethionine 7LP2MPO46S
Mechanistic Target of Rapamycin Complex 1 EC 2.7.11.1
Protein Kinase C EC 2.7.11.13
protein kinase C lambda EC 2.7.11.13

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

385-400.e9

Subventions

Organisme : NIDDK NIH HHS
ID : R01 DK108743
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211794
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207177
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA192642
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA218254
Pays : United States

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

Références

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Auteurs

Miguel Reina-Campos (M)

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.

Juan F Linares (JF)

Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Angeles Duran (A)

Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Thekla Cordes (T)

Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.

Antoine L'Hermitte (A)

Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Mehmet G Badur (MG)

Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.

Munveer S Bhangoo (MS)

Division of Hematology-Oncology Scripps Clinic, 10666 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Phataraporn K Thorson (PK)

Depatment of Pathology, Scripps Clinic Medical Group, 10666 Torrey Pines Road, La Jolla, CA 92037, USA.

Alicia Richards (A)

Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Tarmo Rooslid (T)

Conrad Prebys Center for Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Dolores C Garcia-Olmo (DC)

Centre de Recerca Experimental Biomèdica Aplicada (CREBA), IRBLLEIDA, 25138 Lleida, Spain.

Syongh Y Nam-Cha (SY)

Pathology Department, Director of the Research Unit Biobank, University of Castilla-La Mancha, School of Medicine, 02006 Albacete, Spain.

Antonio S Salinas-Sanchez (AS)

Urology Department, Research Unit, University Hospital Complex of Albacete, School of Medicine, 02006 Albacete, Spain.

Ken Eng (K)

Department of Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.

Himisha Beltran (H)

Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

David A Scott (DA)

Cancer Metabolism Core, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Christian M Metallo (CM)

Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.

Jorge Moscat (J)

Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Maria T Diaz-Meco (MT)

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.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteurs de transcription ATF › Facteur de transcription ATF-4 › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Métabolisme › Voies et réseaux métaboliques › Voies de biosynthèse › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroendocrines › Carcinome neuroendocrine › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation négative › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Isoformes de protéines › Isoenzymes › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Sérine-thréonine kinases TOR › Complexe-1 cible mécanistique de la rapamycine › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Protéine kinase C › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Ribonucléosides › Adénosine › Adémétionine › Increased Serine and One-Carbon Pathway...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés neutres › Sérine › Increased Serine and One-Carbon Pathway...