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Insulin-like Growth Factor 1 Receptor Enhances Invasion and Induces Resistance to Apoptosis of Colon Cancer Cells through the Akt/Bcl-x_L Pathway

Departments of
¹ Interdisciplinary Oncology,
² Pathology,
³ Biostatistics, Moffitt Cancer Center and Research Institute, University of South Florida, College of Medicine, Tampa, Florida 33612

Colon cancer overexpresses insulin-like growth factor 1 (IGF1) and insulin-like growth factor 1 receptor (IGF1-R), as compared with normal or adenomatous mucosa, and it has been postulated that colorectal cancer cells depend on the IGF1/IGF1-R pathway for their growth and progression. In this study, using the human colon cancer cell line HCT116, we find that established HCT116/IGF1-R transfectants exhibit a more aggressive transformed phenotype than the parental cell line, as demonstrated by their higher proliferation rate in response to IGF1, higher degree of anchorage-independent growth, resistance to serum deprivation-induced apoptosis, and higher migratory capability in a monolayer "wounding assay." When injected into nude mice, HCT116/IGF1-R transfectants were highly invasive and produced distant metastases, whereas the parental cell did not. Moreover, the overexpression of IGF1-R in these cells was associated with IGF1-R-induced activation of Akt and up-regulation of the antiapoptotic protein Bcl-x_L. We also show that Akt pathway mediates IGF1-R-induced Bcl-x_L expression at transcriptional level. Our data demonstrate, for the first time, that IGF1-R/Akt/Bcl-x_L pathway may contribute to a more aggressive malignant phenotype, in a subset of colorectal cancers.

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