Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of ErbB2/IGF-1 receptor interactions
Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of ErbB2/IGF-1 receptor interactions
复制标题
DOI：
10.4161/cc.10.17.16359
复制
发表时间：
2011-09-01
期刊：
影响因子：
4.3
通讯作者：
Thor, Ann D.
中科院分区：
文献类型：
--
作者：
Liu, Bolin;Fan, Zeying;Thor, Ann D.
我们已经证明，与三阴性细胞相比，erbB2 改变的乳腺癌细胞对二甲双胍的抗增殖作用不太敏感，并且描述了不同肿瘤亚型的二甲双胍作用的分子机制的差异。我们假设二甲双胍可能对曲妥珠单抗耐药的 erbB2 过表达乳腺癌细胞更有效，因为它针对的是随耐药性而改变的关键信号通路。 BT474、SKBR3 和衍生的曲妥珠单抗耐药亚系 BT474-HR20 (HR20) 和 SKBR3-pool2 (pool2) 用于检验这一假设。二甲双胍治疗导致对耐药亚系的增殖和克隆形成的抑制作用显着增强。它减少了 erbB2/胰岛素样生长因子 1 受体 (IGF-1R) 复合物（仅存在于耐药亚系中），但不改变 erbB2 表达，并降低了曲妥珠单抗耐药细胞（而非亲本细胞）中 erbB3 和 IGF-1R 的表达和活性。曲妥珠单抗耐药亚系对雷帕霉素诱导的 mTO R 活性和细胞生长变化具有耐药性。相比之下，BT474 和 HR20 细胞对 Src (达沙替尼) 和 PI-3K (LY294002) 抑制剂高度敏感。 pool2 细胞对 LY294002 的敏感性高于 SKBR3 细胞，但对达沙替尼则不然。根据这些数据，与敏感的乳腺癌细胞相比，二甲双胍似乎对曲妥珠单抗耐药细胞更有效。二甲双胍会破坏 erbB2/IGF-1R 复合物、erbB3 和 IGF-1R 的表达和活性，以及 Src 激酶和/或 PI-3K/Akt 信号传导。该作用似乎与 mTOR 信号传导无关。我们的研究结果为研究二甲双胍对接受曲妥珠单抗治疗（无论是否耐药）的 erbB2 阳性肿瘤患者的影响提供了理论依据。
We have shown that erbB2 altered breast cancer cells are less sensitive to the anti-proliferative effects of metformin than triple negative cells, and have described the differences of molecular mechanisms of metformin action by tumor subtypes. We hypothesized that metformin may be more effective against trastuzumab-resistant erbB2-overexpressing breast cancer cells because it targets the critical signaling pathways that are altered with resistance. BT474, SKBR3 and derived trastuzumab-resistant sublines BT474-HR20 (HR20) and SKBR3-pool2 (pool2) were used to test this hypothesis. Metformin treatment resulted in significantly more inhibition of proliferation and clonogenicity in resistant sublines. It decreased erbB2/insulin-like growth factor-1 receptor (IGF-1R) complexes (present only in the resistant sublines) without altering erbB2 expression and reduced the expression and activity of erbB3 and IGF-1R in the trastuzumab-resistant but not parental cells. Trastuzumab-resistant sublines were resistant to rapamycin induced changes in mTO R activity and cell growth. In contrast, both BT474 and HR20 cells were highly sensitive to inhibitors of Src (Dasatinib) and PI-3K (LY294002). The pool2 cells showed higher sensitivity than SKBR3 cells to LY294002, but not Dasatinib. On the basis of these data, metformin appears to be significantly more effective against trastuzumab-resistant as compared with sensitive breast cancer cells. Metformin disrupts erbB2/IGF-1R complexes, erbB3 and IGF-1R expression and activity, as well as Src kinase and/or PI-3K/Akt signaling. This action appears to be independent of mTO R signaling. Our findings provide a rationale to study the effects of metformin on patients with erbB2 positive tumors treated with trastuzumab, with or without resistance.