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Functional Insulin Receptors on Human Epithelial Ovarian Carcinoma Cells: Implications for IGF-II Mitogenic Signaling

Division of Endocrinology and Metabolism, Endocrine Research Unit (K.R.K., O.I.F., L.K.B., C.A.C.) and Division of Experimental Pathology (M.A.Z., P.C.R.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Dr. Cheryl Conover, Endocrine Research Unit, Mayo Clinic, 200 First Street Southwest, 5-194 Joseph, Rochester, Minnesota 55905. E-mail: conover.cheryl{at}mayo.edu.

The insulin receptor mediates a proliferative response in certain transformed cells, but little is known about its function in ovarian cancer. We used human epithelial ovarian carcinoma cell lines and lifespan-extended normal ovarian surface epithelial (OSE) cells to examine ¹²⁵I-insulin binding and mitogenic responses to insulin. All cancer cell and OSE cultures specifically bound ¹²⁵I-insulin. Except for OV202, the carcinoma lines had elevated insulin binding compared with OSE cells. All carcinoma lines except OV202 expressed insulin receptor as detected by flow cytometry and increased ³H-thymidine incorporation or cell number in response to 0.1–10 nM insulin. Interestingly, similar concentrations of IGF-II also induced proliferation of the insulin-responsive cancer cell lines and displaced ¹²⁵I-insulin binding. Direct binding of ¹²⁵I-IGF-II to the insulin receptor was visualized by cross-linking and immunoprecipitation. Binding of IGF-II to the insulin receptor and a proliferative effect of insulin suggest the presence of insulin receptor isoform A. Real-time PCR analyses confirm that insulin receptor isoform A expression predominates over isoform B expression in the ovarian carcinoma cell lines. This report suggests that the insulin receptor may play a role in the regulation of ovarian cancer cell growth.

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