Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
Oncol Res. 2011;19(6):275-85. doi: 10.3727/096504011x13021877989838.
Metformin is the most widely used antidiabetic drug for type II diabetes in the world. Recent studies provide clues that the use of metformin may be associated with reduced incidence and improved prognosis of certain cancers and there is increasing evidence of a potential efficacy of this agent as an anticancer drug. This observation led us to hypothesize that metformin might inhibit human breast cancer cells (MCF-7) growth. Here, we report that metformin induced apoptosis in human breast carcinoma cell lines MCF-7 cells via novel signaling pathway. Metformin induced apoptosis by arresting cells in G1 phase and reducing cyclin D level and increasing the expression of p21 and cyclin E. Molecular and cellular studies indicated that metformin significantly elevated p53 and Bax levels and reduced STAT3 and Bcl-2. Inhibitors of signaling proteins were used to study the mechanism(s) of metformin function. Receptor inhibitor studies indicated that p53 activation was mediated through insulin receptor (IR), not insulin-like growth factor-1 receptor (IGF-IR). Furthermore, MEK inhibitor significantly suppressed metformin-induced p53 and Bax elevation while ERK inhibitor generated a slight reduction in p53 levels. In contrast, PI3K inhibitor did not produce any effect on the metformin-elevated p53 levels. Finally, SAPK/JNK, known to be involved in apoptosis, was activated in cells treated with metformin and the activation appeared to occur downstream of ERK. All these results suggested that metformin activated p53, Bax, and induced tumor cell apoptosis through the ERK signaling pathway. This pathway has not been previously described for IR, p53, Bax activation, or apoptosis. Metformin, a novel inducer of apoptosis, and its analogs may offer a novel strategy for the treatment of cancer cells.
二甲双胍是世界上用于治疗 2 型糖尿病最广泛的抗糖尿病药物。最近的研究提供了线索，表明二甲双胍的使用可能与某些癌症的发病率降低和预后改善有关，并且越来越多的证据表明该药物作为抗癌药物具有潜在的疗效。这一观察结果使我们假设二甲双胍可能抑制人乳腺癌细胞（MCF-7）的生长。在这里，我们报告二甲双胍通过新的信号通路诱导人乳腺癌细胞系 MCF-7 细胞凋亡。二甲双胍通过将细胞阻滞在 G1 期，降低 cyclin D 水平并增加 p21 和 cyclin E 的表达来诱导细胞凋亡。分子和细胞研究表明，二甲双胍显著提高了 p53 和 Bax 的水平，降低了 STAT3 和 Bcl-2 的水平。使用信号蛋白抑制剂来研究二甲双胍作用的机制。受体抑制剂研究表明，p53 的激活是通过胰岛素受体（IR）介导的，而不是胰岛素样生长因子-1 受体（IGF-1R）介导的。此外，MEK 抑制剂显著抑制了二甲双胍诱导的 p53 和 Bax 升高，而 ERK 抑制剂则使 p53 水平略有降低。相反，PI3K 抑制剂对二甲双胍升高的 p53 水平没有任何影响。最后，SAPK/JNK，已知参与凋亡，在接受二甲双胍治疗的细胞中被激活，并且这种激活似乎发生在 ERK 之后。所有这些结果表明，二甲双胍通过 ERK 信号通路激活了 p53、Bax，并诱导肿瘤细胞凋亡。该通路以前没有被描述过用于 IR、p53、Bax 激活或凋亡。二甲双胍是一种新的凋亡诱导剂，及其类似物可能为治疗癌细胞提供一种新的策略。
