Title | The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Linares 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 |
Journal | Cell Rep |
Volume | 39 |
Issue | 6 |
Pagination | 110792 |
Date Published | 2022 May 10 |
ISSN | 2211-1247 |
Keywords | Cancer-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. |
DOI | 10.1016/j.celrep.2022.110792 |
Alternate Journal | Cell Rep |
PubMed ID | 35545049 |
PubMed Central ID | PMC9136538 |
Grant List | P30 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.