The lactate-NAD+ axis activates cancer-associated fibroblasts by downregulating p62. Academic Article uri icon

Overview

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.

publication date

  • May 10, 2022

Research

keywords

  • Cancer-Associated Fibroblasts
  • Neoplasms

Identity

PubMed Central ID

  • PMC9136538

Scopus Document Identifier

  • 85129909308

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2020.06.005

PubMed ID

  • 35545049

Additional Document Info

volume

  • 39

issue

  • 6