Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death.
Animals
Apoptosis
/ drug effects
Cell Death
/ drug effects
Fibroblast Growth Factor 2
/ metabolism
Gene Expression Regulation, Neoplastic
HEK293 Cells
HeLa Cells
Humans
Mice
Mice, Inbred C57BL
Myeloid Cell Leukemia Sequence 1 Protein
/ metabolism
Proto-Oncogene Proteins c-bcl-2
/ metabolism
Signal Transduction
/ drug effects
Up-Regulation
/ drug effects
Wound Healing
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 11 2021
12 11 2021
Historique:
received:
10
08
2020
accepted:
08
10
2021
entrez:
13
11
2021
pubmed:
14
11
2021
medline:
15
12
2021
Statut:
epublish
Résumé
Damaged or superfluous cells are typically eliminated by apoptosis. Although apoptosis is a cell-autonomous process, apoptotic cells communicate with their environment in different ways. Here we describe a mechanism whereby cells under apoptotic stress can promote survival of neighbouring cells. We find that upon apoptotic stress, cells release the growth factor FGF2, leading to MEK-ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of pro-survival BCL-2 proteins protects neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. In vivo, upregulation of MCL-1 occurs in an FGF-dependent manner during skin repair, which regulates healing dynamics. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity to cytotoxic therapy and delays wound healing. These data reveal a pathway by which cells under apoptotic stress can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process also provides a potential link between tissue damage and repair.
Identifiants
pubmed: 34772930
doi: 10.1038/s41467-021-26613-0
pii: 10.1038/s41467-021-26613-0
pmc: PMC8590049
doi:
Substances chimiques
MCL1 protein, human
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Proto-Oncogene Proteins c-bcl-2
0
Fibroblast Growth Factor 2
103107-01-3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6572Subventions
Organisme : Cancer Research UK
ID : C40872/A2014
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C596/A17196
Pays : United Kingdom
Informations de copyright
© 2021. The Author(s).
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