Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation.
Cell Proliferation
/ drug effects
Cells, Cultured
Class I Phosphatidylinositol 3-Kinases
/ genetics
Drug Discovery
Fibroblasts
/ drug effects
Heat Shock Transcription Factors
/ antagonists & inhibitors
Humans
Lipoma
/ drug therapy
Molecular Targeted Therapy
Musculoskeletal Abnormalities
/ drug therapy
Mutation
Nevus
/ drug therapy
Phosphorylation
/ drug effects
Proto-Oncogene Proteins c-akt
/ antagonists & inhibitors
Signal Transduction
/ drug effects
Vascular Malformations
/ drug therapy
HSF1
PI3K
Segmental overgrowth spectrum
Journal
Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516
Informations de publication
Date de publication:
24 09 2020
24 09 2020
Historique:
received:
09
04
2020
accepted:
29
04
2020
pubmed:
6
7
2020
medline:
17
3
2021
entrez:
5
7
2020
Statut:
ppublish
Résumé
PIK3CA-related overgrowth spectrum is caused by mosaicism mutations in the PIK3CA gene. These mutations, which are also observed in various types of cancer, lead to a constitutive activation of the PI3K/AKT/mTOR pathway, increasing cell proliferation. Heat shock transcription factor 1 (HSF1) is the major stress-responsive transcription factor. Recent findings indicate that AKT phosphorylates and activates HSF1 independently of heat-shock in breast cancer cells. Here, we aimed to investigate the role of HSF1 in PIK3CA-related overgrowth spectrum. We observed a higher rate of proliferation and increased phosphorylation of AKT and p70S6K in mutant fibroblasts than in control cells. We also found elevated phosphorylation and activation of HSF1, which is directly correlated to AKT activation. Specific AKT inhibitors inhibit HSF1 phosphorylation as well as HSF1-dependent gene transcription. Finally, we demonstrated that targeting HSF1 with specific inhibitors reduced the proliferation of mutant cells. As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target.
Identifiants
pubmed: 32620236
pii: S0006-291X(20)30886-X
doi: 10.1016/j.bbrc.2020.04.146
pii:
doi:
Substances chimiques
HSF1 protein, human
0
Heat Shock Transcription Factors
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
520-526Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.