Proliferative and signaling activities of insulin analogues in endometrial cancer cells

• The potential mitogenic actions of insulin analogues are the topic of controversy.
• Glargine, but not detemir, stimulates endometrial cancer cell proliferation.
• Glargine induces dual activation of the INSR and IGF1R in endometrial cancer cells.
• Glargine and detemir elicit atypical signaling different from that induced by insulin.
• Glargine exhibits IGF1-like mitogenic and signaling activities.

Insulin analogues have been developed to achieve further improvement in the therapy of diabetes. However, modifications introduced into the insulin molecule may enhance their affinity for the insulin-like growth factor-1 receptor (IGF1R). Hyperinsulinemia has been identified as a risk factor for endometrial cancer. We hypothesized that insulin analogues may elicit atypical proliferative and signaling activities in endometrial cancer cells. Our results demonstrate that glargine, but not detemir, stimulated cell proliferation, displayed an anti-apoptotic effect, and had a positive effect on cell cycle progression in endometrial cancer cell lines ECC-1 and USPC-1. In addition, we showed that glargine and detemir induced dual activation of the insulin receptor (INSR) and IGF1R in both cell types. Furthermore, we showed that glargine elicited signaling events that are markedly different from those induced by insulin. In conclusion, our data support the concept that, although insulin analogues were designed to display insulin-like metabolic effects, glargine and, possibly, additional analogues exhibit IGF1-like activities and, accordingly, may function as IGF1 analogues.