Metformin Causes G1-Phase Arrest via Down-Regulation of MiR-221 and Enhances TRAIL Sensitivity through DR5 Up-Regulation in Pancreatic Cancer Cells.
Metformin Causes G1-Phase Arrest via Down-Regulation of MiR-221 and Enhances TRAIL Sensitivity through DR5 Up-Regulation in Pancreatic Cancer Cells.
复制标题
DOI：
10.1371/journal.pone.0125779
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sakai T
中科院分区：
文献类型：
--
作者：
Tanaka R;Tomosugi M;Horinaka M;Sowa Y;Sakai T
虽然已经开发了许多针对癌症的化学治疗策略，但胰腺癌是最具侵袭性和最难治性的恶性肿瘤类型之一。因此，需要新的策略和抗癌药物来治疗这种疾病。二甲双胍是一种广泛应用于2型糖尿病的药物，并且从最近的体外和体内研究中也被认为是一种有前途的候选抗癌药物。然而，二甲双胍抗癌作用的机制尚未阐明。我们证明二甲双胍抑制了人胰腺癌PANC-1细胞中最知名的致癌microRNA之一miR-221的表达。此外，我们发现二甲双胍下调miR-221通过上调p27（miR-221的直接靶点之一）导致G1期阻滞。肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）也是一种很有前途的肿瘤治疗药物。虽然最近的研究表明，仅用TRAIL治疗对胰腺癌细胞无效，但目前的数据显示二甲双胍使p53突变的胰腺癌细胞对TRAIL敏感。二甲双胍诱导TRAIL受体死亡受体5（DR 5）和在TRAIL-DR 5通路下游具有促凋亡功能的Bim的表达。我们认为，这些蛋白的上调可能有助于敏化TRAIL诱导的细胞凋亡。因此，二甲双胍和TRAIL的联合治疗可以有效治疗胰腺癌。
Although many chemotherapeutic strategies against cancer have been developed, pancreatic cancer is one of the most aggressive and intractable types of malignancies. Therefore, new strategies and anti-cancer agents are necessary to treat this disease. Metformin is a widely used drug for type-2 diabetes, and is also known as a promising candidate anti-cancer agent from recent studies in vitro and in vivo. However, the mechanisms of metformin’s anti-cancer effects have not been elucidated. We demonstrated that metformin suppressed the expression of miR-221, one of the most well-known oncogenic microRNAs, in human pancreatic cancer PANC-1 cells. Moreover, we showed that the down-regulation of miR-221 by metformin caused G1-phase arrest via the up-regulation of p27, one of the direct targets of miR-221. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is also a promising agent for cancer treatment. While recent studies showed that treatment with only TRAIL was not effective against pancreatic cancer cells, the present data showed that metformin sensitized p53-mutated pancreatic cancer cells to TRAIL. Metformin induced the expressions of death receptor 5 (DR5), a receptor for TRAIL, and Bim with a pro-apoptotic function in the downstream of TRAIL-DR5 pathway. We suggest that the up-regulation of these proteins may contribute to sensitization of TRAIL-induced apoptosis. The combination therapy of metformin and TRAIL could therefore be effective in the treatment of pancreatic cancer.