Cellular radiosensitivity and endocytosis: The role of PINCH1 and caveolin-1.

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In normal and cancer cells, endocytosis plays a fundamental role in various cell functions such as survival, proliferation, metabolism, migration and signal transduction. Tissue-specifically, the integral membrane proteins caveolin-1, -2 and -3 are responsible for caveolae-mediated endocytosis. Caveolin-1 is linked to integrin adhesion and growth factor receptors and controls the caveolae formation in an Integrin-linked kinase (ILK) manner. For PINCH1, which controls focal adhesion assembly together with ILK and Parvin (IPP protein complex), a role in caveolin-1-dependent endocytosis remains elusive. Own preliminary data show that caveolin-1 and PINCH1 interact and that both proteins are over-expressed in malignant tumors. Both, PINCH1 and caveolin-1 interact with the protein kinase Akt1 for the regulation of radio- and chemoresistance mechanisms. By means of targeted inhibition of PINCH1 and caveolin-1, we were able to significantly reduce radio- and chemoresistance in cells originating from different cancer types. However, it remains elusive what influence ionizing radiation and chemotherapeutics have on caveolin-1-dependent endocytosis and which function PINCH1, as part of the IPP complex, has in this process. The proposed project addresses the molecular mechanisms of caveolin-1-dependent endocytosis and the contribution of PINCH1 upon radiotherapy in mouse embryonic PINCH1-/- fibroblasts reconstituted with different PINCH1 variants and in cell cultures from ductal adenocarcinomas of the pancreas. Through the identification of the endocytosis regulation in dependence on PINCH1 upon radiotherapy, new insights into the resistance mechanisms and associated signaling pathways in malignant tumors as well as the identification of novel potential therapeutic strategies in combination with radiotherapy are anticipated.