Séminaire IBS : The transport activity of Ptch1 in Hedgehog signaling regulation and in chemotherapy resistance of cancer cells

Par Dr Isabelle Mus-Veteau (Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Valbonne)

The 12 transmembrane helices protein Ptch1 regulates the GPCR Smoothened and the Hedgehog signaling by transporting cholesterol. Hedgehog signaling is aberrantly activated and Ptch1 is overexpressed in many recurrent and metastatic cancers. We showed that Ptch1pumps chemotherapeutic agents such as doxorubicin out of cancer cells using the proton motive force and contributes to chemotherapy resistance of several cancer cell types, and that cells overexpressing Ptch1 at their plasma membrane have cancer stem cell properties.

We identified a small molecule which inhibits the doxorubicin efflux activity of Ptch1 and enhance its cytotoxicity in different cancer cell lines endogenously overexpressing Ptch1, and thereby mitigates the resistance of these cancer cells to doxorubicin. We also showed that this Ptch1 drug efflux inhibitor enhances the efficacy of kinase inhibitors such as vemurafenib against melanoma cells resistant to the treatment in cellulo and in vivo on xenografts in mice. Data obtained from microscale thermophoresis and in silico (docking and molecular dynamics) strongly support that this drug efflux inhibitor interacts directly with Ptch1.

Altogether, our data suggest that the use of inhibitors of Ptch1 drug efflux in combination with chemotherapy could be a promising therapeutic option to improve chemotherapy efficiency against cancer cells expressing Ptch1.

Hôte : Christophe Moreau (IBS/MEMBRANE)