The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62.

TitleThe lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62.
Publication TypeJournal Article
Year of Publication2022
AuthorsLinares JF, Cid-Diaz T, Duran A, Osrodek M, Martinez-Ordoñez A, Reina-Campos M, Kuo H-H, Elemento O, M Martin L, Cordes T, Thompson TC, Metallo CM, Moscat J, Diaz-Meco MT
JournalCell Rep
Volume39
Issue6
Pagination110792
Date Published2022 May 10
ISSN2211-1247
KeywordsCancer-Associated Fibroblasts, Fibroblasts, Lactic Acid, NAD, Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases
Abstract

Reduced p62 levels are associated with the induction of the cancer-associated fibroblast (CAF) phenotype, which promotes tumorigenesis in vitro and in vivo through inflammation and metabolic reprogramming. However, how p62 is downregulated in the stroma fibroblasts by tumor cells to drive CAF activation is an unresolved central issue in the field. Here we show that tumor-secreted lactate downregulates p62 transcriptionally through a mechanism involving reduction of the NAD+/NADH ratio, which impairs poly(ADP-ribose)-polymerase 1 (PARP-1) activity. PARP-1 inhibition blocks the poly(ADP-ribosyl)ation of the AP-1 transcription factors, c-FOS and c-JUN, which is an obligate step for p62 downregulation. Importantly, restoring p62 levels in CAFs by NAD+ renders CAFs less active. PARP inhibitors, such as olaparib, mimick lactate in the reduction of stromal p62 levels, as well as the subsequent stromal activation both in vitro and in vivo, which suggests that therapies using olaparib would benefit from strategies aimed at inhibiting CAF activity.

DOI10.1016/j.celrep.2022.110792
Alternate JournalCell Rep
PubMed ID35545049
PubMed Central IDPMC9136538
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
P30 CA030199 / CA / NCI NIH HHS / United States
P50 CA211024 / CA / NCI NIH HHS / United States
R50 CA252146 / CA / NCI NIH HHS / United States
R01 CA250025 / CA / NCI NIH HHS / United States
R01 CA218254 / CA / NCI NIH HHS / United States
R01 CA234245 / CA / NCI NIH HHS / United States
R01 CA265892 / CA / NCI NIH HHS / United States
R01 CA246765 / CA / NCI NIH HHS / United States
P30 CA014195 / CA / NCI NIH HHS / United States
Related Faculty: 
Maria Angeles Duran, Ph.D. Juan Francisco Linares Rodriguez, Ph.D. Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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