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

在正常细胞和癌细胞中，内吞作用在各种细胞功能如存活、增殖、代谢、迁移和信号转导中起着基本作用。组织特异性地，膜蛋白小窝蛋白-1、-2和-3负责小窝介导的内吞。小窝蛋白-1与整合素粘附和生长因子受体连接，并以整合素连接激酶（ILK）的方式控制小窝的形成。PINCH 1与ILK和Parvin（IPP蛋白复合物）一起控制粘着斑组装，其在小窝蛋白-1依赖性内吞作用中的作用仍然难以捉摸。自己的初步数据表明，小窝蛋白-1和PINCH 1相互作用，并且这两种蛋白质在恶性肿瘤中过度表达。PINCH 1和小窝蛋白-1都与蛋白激酶Akt 1相互作用，以调节放射性和化学抗性机制。通过靶向抑制PINCH 1和caveolin-1，我们能够显著降低来自不同癌症类型的细胞的放射性和化学抗性。然而，电离辐射和化疗药物对小窝蛋白-1依赖性内吞作用的影响以及PINCH 1作为IPP复合物的一部分在该过程中的功能仍然是难以捉摸的。拟议的项目解决了小窝蛋白-1依赖的内吞作用的分子机制和PINCH 1的贡献后，在小鼠胚胎PINCH 1-/-成纤维细胞与不同的PINCH 1变体重建和胰腺导管腺癌的细胞培养物中的放射治疗。通过识别依赖于PINCH 1的内吞调节在放射治疗后，恶性肿瘤的耐药机制和相关的信号通路的新见解，以及识别新的潜在的治疗策略与放射治疗相结合的预期。

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.