Aizen Daniel, Sarfstein Rive, Bruchim Ilan, Weinstein Doron, Laron Zvi, Werner Haim
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel.
Mol Cell Endocrinol. 2015 May 5;406:27-39. doi: 10.1016/j.mce.2015.02.011. Epub 2015 Feb 16.
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.
胰岛素类似物已被开发出来，以进一步改善糖尿病的治疗。然而，对胰岛素分子进行的修饰可能会增强其对胰岛素样生长因子-1受体（IGF1R）的亲和力。高胰岛素血症已被确定为子宫内膜癌的一个危险因素。我们假设胰岛素类似物可能会在子宫内膜癌细胞中引发非典型的增殖和信号传导活动。我们的结果表明，甘精胰岛素，但不是地特胰岛素，刺激了细胞增殖，显示出抗凋亡作用，并对子宫内膜癌细胞系ECC-1和USPC-1的细胞周期进程有积极影响。此外，我们表明甘精胰岛素和地特胰岛素在这两种细胞类型中都诱导了胰岛素受体（INSR）和IGF1R的双重激活。此外，我们表明甘精胰岛素引发的信号事件与胰岛素诱导的信号事件明显不同。总之，我们的数据支持这样一个概念，即尽管胰岛素类似物旨在表现出胰岛素样的代谢作用，但甘精胰岛素以及可能的其他类似物表现出IGF1样的活性，因此可能作为IGF1类似物发挥作用。
