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

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

  • Biochem Biophys Res Commun. 2020 Sep 24;530(3):520-526. doi: 10.1016/j.bbrc.2020.04.146.
Romain Da Costa 1,  Steven De Almeida 2,  Martin Chevarin 1,  Smail Hadj-Rabia 3,  Stéphanie Leclerc-Mercier 4,  Christel Thauvin-Robinet 1,  Carmen Garrido 2,  Laurence Faivre 1,  Pierre Vabres 5,  Laurence Duplomb 1,  Gaëtan Jego 6
Affiliations

Affiliations

  • 1 INSERM, LNC UMR1231, Team GAD, University of Burgundy and Franche-Comté, F-21000, Dijon, France; FHU-TRANSLAD, University of Burgundy and Franche-Comté, Dijon University Hospital, F-21000, Dijon, France.
  • 2 INSERM, LNC UMR1231 Team HSP-pathies, University of Burgundy and Franche-Comté, F-21000, Dijon, France.
  • 3 Department of Dermatology, Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Hôpital Universitaire Necker- Enfants Malades, Assistance Publique - Hôpitaux de Paris-Centre (AP-HP5), Paris, France.
  • 4 Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
  • 5 INSERM, LNC UMR1231, Team GAD, University of Burgundy and Franche-Comté, F-21000, Dijon, France; FHU-TRANSLAD, University of Burgundy and Franche-Comté, Dijon University Hospital, F-21000, Dijon, France; Department of Dermatology, Dijon University Hospital, F-21000, Dijon, France.
  • 6 INSERM, LNC UMR1231 Team HSP-pathies, University of Burgundy and Franche-Comté, F-21000, Dijon, France. Electronic address: gaetan.jego@u-bourgogne.fr.
PMID: 32620236 DOI: 10.1016/j.bbrc.2020.04.146
Abstract

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.

Keywords

HSF1; PI3K; Segmental overgrowth spectrum.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15244
    99.95%, PI3Kα抑制剂
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