Abstract #5048: Deoxycholic acid induces endocytosis of the insulin-like growth factor-I receptor in colorectal cancer cells

Deoxycholic acid (DCA) is postulated to promote the progression of colorectal cancer, but its specific mechanisms have not been fully elucidated. DCA can induce apoptosis, which allows it to select for apoptosis-resistant colon cells. This emphasizes the importance of understanding the mechanisms that grant some colon cells resistance to the cytotoxic effects of DCA. Because the insulin-like growth factor-I receptor (IGF-IR) has been shown to protect colorectal cancer cells from apoptosis, we hypothesized that it may protect against DCA's cytotoxicity and select for the survival of apoptosis-resistant cells. We tested several colorectal cancer cell lines for their sensitivity to the cytotoxic effects of DCA, and focused our efforts on HT29 and HCT116. We found that IGF-I significantly reduced the level of the DCA-induced apoptosis, implicating IGF-IR in protecting against the cytotoxicity of DCA. We demonstrated that DCA caused the endocytosis of IGF-IR in HT29 and HCT116. When endocytosis was inhibited, HT29 and HCT116 were more resistant to the cytotoxic effects of DCA. The specific mechanisms of the DCA-induced endocytosis of IGF-IR will be discussed, but we have shown that both clathrin and caveolin-1 endocytic mechanisms have been implicated. In conclusion, we show that DCA induced the endocytosis of IGF-IR in HT29 and HCT116, which sensitized these cells to the DCA-induced apoptosis. This work demonstrates a novel mechanism through which DCA can select for apoptosis-resistant cells. Understanding the mechanisms that induce apoptosis and mechanisms that protect against the cytotoxic effects of DCA are significant, since they could lead to the development of novel therapeutic strategies to sensitize apoptosis-resistant cells.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5048.