Overexpression of the Insulin Receptor Isoform A Promotes Endometrial Carcinoma Cell Growth

Abstract

Epidemiological studies have demonstrated that type 2 diabetes mellitus (T2DM) and hyperinsulinemia are associated closely with endometrial carcinoma risk, although the molecular mechanism remains unclear. Insulin receptor isoformA expression is upregulated in many cancer cells and tissues, which suggests that IR-A-mediated signaling pathways may have important implications for cancer pathogenesis. We measured the expression of insulin receptor isoforms (IR-A and IR–B in the normal endometrium tissues, the endometrial carcinoma tissues and the endometrial carcinoma cell lines. We found that the total insulin receptor (IR) and IR-A expression mRNA levels and the ratio of IR-A to total IR in endometrial carcinoma specimens were significantly higher than them in control endometrial tissue specimens(P<0.05). Further analysis indicated that the tendency was more prominently in patients with T2DM. IR-A mRNA was differentially expressed in four endometrial carcinoma cell lines (Ishikawa, KLE, RL95-2 and HEC-1-A. RL95-2 cells have a low endogenous IR-A expression, and these were used to construct a stable cell line overexpressing IR-A. We found that IR-A overexpression significantly increased cell proliferation, the proportion of cells in S phase, activation of the Akt pathway and tumorigenicity of xenografts in nude mice. In contrast, there was no significant difference in the the percentage of apoptotic cells between cells overexpressing IR-A and control cells. Moreover, levels of phosphorylated ERK1/2 protein were significantly decreased in cells overexpressing IR-A relative to controls. These findings reveal the pivotal role of IR-A in endometrial cancer carcinogenesis, and suggest that the association of elevated IR-A levels with cell proliferation and tumorigenicity may be causally linked to its effect on the proportion of cells in S phase and the activation of the Akt pathway.

Use of Metformin in Obese Women With Type I Endometrial Cancer Is Associated With a Reduced Incidence of Cancer Recurrence

“…21 Insulin can bind to IGF receptors in the endometrium, which have been associated with the development of endometrial cancer. 22 In addition, insulin can inhibit the synthesis of sex hormoneYbinding globulin, which results in an increase in free circulating estrogens. 23 Metformin is a biguanine used in the treatment of type II diabetes.…”

Metformin use and gynecological cancers: A novel treatment option emerging from drug repositioning

“…Estrogen also increases endometrial IGF-1R synthesis (86), and over-expression of insulin receptor [IR] and IGF-1R can promote endometrial carcinogenesis (87,88). Moreover IGF-1 reduces PR expression in endometrial cancer cell lines (89).…”

Insulin-Like Growth Factor 1/Mammalian Target of Rapamycin and AMP-Activated Protein Kinase Signaling Involved in the Effects of Metformin in the Human Endometrial Cancer

“…Alteration of the PI3K/AKT/mTOR pathway is heavily implicated in EC pathogenesis, it is necessary to identify mechanistic feedback loops and crosstalk with other signaling cascades to anticipate mechanisms of adaptive response and acquired resistance and thereby to develop rational therapeutic approach. A number of in vitro studies have demonstrated the antiproliferative, anti-invasive, and antimetastatic effects of metformin in multiple cancer cell types, including EC-like cancer cells, 15 but there is presently insufficient data available to justify use of metformin as a preventive or as an anticancer agent in EC. On the basis of in vitro studies and rodent models, our goal was to investigate anticancer effects of metformin involved in IGF-1, mTOR, and AMPK signaling in nondiabetic women with EC who were candidates to surgery.…”