title: Insulin receptor compensates for IGF1R inhibition and directly induces mitogenic activity in prostate cancer cells.
abstract: Hyperinsulinemia is a major complication associated with the development of insulin resistance. In addition to its normal spectrum of metabolic effects, insulin can act as a growth factor and has the ability to promote mitogenic activity. Thus, hyperinsulinemia is regarded as a potentially important cancer risk factor among diabetic patients. However, the mechanisms of action of insulin in the specific context of prostate cancer (PCa) and, in particular, the specific receptor that mediates its actions have not been elucidated yet. The aims of this study were to investigate whether insulin can directly induce mitogenic activities in PCa-derived cell lines and to examine the mechanisms responsible for these actions. To this end, we used several PCa-derived cell lines, representing early and advanced stages of the disease. Our results indicated that insulin induces cell proliferation in a dose-dependent fashion in the LNCaP, C4-2, and P69 cell lines. We also demonstrated that insulin enabled LNCaP and C4-2 cells to progress through the cell cycle. Immunoprecipitation assays revealed that insulin activated the insulin receptor (INSR), but not the IGF1 receptor (IGF1R). In addition, INSR was able to compensate for and mediate IGF1 mitogenic signals following IGF1R inhibition. In conclusion, insulin exhibits direct mitogenic activities in PCa cells, which are mediated exclusively through the INSR. Further research is needed to fully dissect the molecular mechanisms underlying the biological actions of insulin in PCa.
authors.affiliation: Department of Human Molecular Genetics and BiochemistrySackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel Endocrinology and Diabetes Research UnitSchneider Children's Medical Center, Petah Tikva 49202, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Weinstein
authors.forename: Rive
authors.initials: R
authors.lastname: Sarfstein
authors.forename: Zvi
authors.initials: Z
authors.lastname: Laron
authors.forename: Haim
authors.initials: H
authors.lastname: Werner
keywords: IGF1 receptor; insulin; insulin receptor; insulin-like growth factor-1 (IGF1); prostate cancer