Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation.

Fiche publication

Date publication

juin 2020

Journal

Biochemical and biophysical research communications

Auteurs

Membres identifiés du Cancéropôle Est :
Dr GARRIDO Carmen , Pr FAIVRE Laurence , Pr VABRES Pierre , Dr JEGO Gaëtan , Pr THAUVIN-ROBINET Christel , Dr DUPLOMB-JEGO Laurence

Tous les auteurs :
Da Costa R, De Almeida S, Chevarin M, Hadj-Rabia S, Leclerc-Mercier S, Thauvin-Robinet C, Garrido C, Faivre L, Vabres P, Duplomb L, Jego G

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/32620236

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.