在子宫内膜癌细胞中二甲双胍通过干扰IGF-IR信号轴显示抗增殖活性

METFORMIN DISPLAYS ANTIPROLIFERATIVE ACTIVITIES IN ENDOMETRIAL CANCER CELLS VIA INTERACTION WITH THE IGF-IR SIGNALING AXIS

Background: Studies have shown a correlation between obesity and endometrial cancer risk. Metformin is an anti-diabetes drug with potential anti-neoplastic actions. The aim of this study was to evaluate whether the antiproliferative actions of metformin are potentially mediated via suppression of the IGF-I receptor pathway.
Materials and methods: Human endometrioid Ishikawa and ECC (Type I) and serous (USPC-2 and USPC-1; Type II) endometrial cancer cell lines were treated with metformin (10 mM), in the presence or absence of IGF-I. The expression and activation of specific genes involved in IGF signaling was evaluated by Western blotting. Apoptosis was evaluated by cleavage of PARP, caspase-3, and Bcl2 measurements. Cell viability was measured by MTT assays.
Results: Metformin decreased the IGF-I stimulated phosphorylation of IGF-IR in ECC-1, USPC-1 and USPC-2 cells. Metformin up-regulated AKT and ERK1/2 phosphorylation in Ishikawa, ECC-1 and USPC-1 cells and down-regulated them in USPC-2 cells. Metformin down-regulated the expression of total IGF-IR and insulin receptor in USPC-1 cells and up-regulated IGF-IR levels in ECC-1 cells. In addition, the data showed that metformin induced a significant increase in cleaved PARP in USPC-1 and USPC-2 cells. Finally, MTT assays showed that metformin caused a decrease in proliferation rate compared with control cells.
Conclusions: In summary, our studies demonstrate that metformin displays potent apoptotic and anti-mitogenic actions in endometrial cancer cells that are mediated, at least partially, via interaction with the IGF-IR axis. Taken together, our results suggest that rational use of metformin may help reduce endometrial cancer risk.

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