Liu Chun-Yu, Hu Ming-Hung, Hsu Chia-Jung, Huang Chun-Teng, Wang Duen-Shian, Tsai Wen-Chun, Chen Yi-Ting, Lee Chia-Han, Chu Pei-Yi, Hsu Chia-Chi, Chen Ming-Huang, Shiau Chung-Wai, Tseng Ling-Ming, Chen Kuen-Feng
Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Oncotarget. 2016 Feb 23;7(8):9135-49. doi: 10.18632/oncotarget.7035.
We tested the efficacy of lapatinib, a dual tyrosine kinase inhibitor which interrupts the HER2 and epidermal growth factor receptor (EGFR) pathways, in a panel of triple-negative breast cancer (TNBC) cells, and examined the drug mechanism. Lapatinib showed an anti-proliferative effect in HCC 1937, MDA-MB-468, and MDA-MB-231 cell lines. Lapatinib induced significant apoptosis and inhibited CIP2A and p-Akt in a dose and time-dependent manner in the three TNBC cell lines. Overexpression of CIP2A reduced lapatinib-induced apoptosis in MDA-MB-468 cells. In addition, lapatinib increased PP2A activity (in relation to CIP2A inhibition). Moreover, lapatinib-induced apoptosis and p-Akt downregulation was attenuated by PP2A antagonist okadaic acid. Furthermore, lapatinib indirectly decreased CIP2A transcription by disturbing the binding of Elk1 to the CIP2A promoter. Importantly, lapatinib showed anti-tumor activity in mice bearing MDA-MB-468 xenograft tumors, and suppressed CIP2A as well as p-Akt in these xenografted tumors. In summary, inhibition of CIP2A determines the effects of lapatinib-induced apoptosis in TNBC cells. In addition to being a dual tyrosine kinase inhibitor of HER2 and EGFR, lapatinib also inhibits CIP2A/PP2A/p-Akt signaling in TNBC cells.
我们在一组三阴性乳腺癌（TNBC）细胞中测试了拉帕替尼（一种可阻断HER2和表皮生长因子受体（EGFR）信号通路的双靶点酪氨酸激酶抑制剂）的疗效，并研究了其作用机制。拉帕替尼在HCC 1937、MDA-MB-468和MDA-MB-231细胞系中显示出抗增殖作用。拉帕替尼在这三种TNBC细胞系中以剂量和时间依赖性方式诱导显著凋亡，并抑制CIP2A和p-Akt。CIP2A的过表达减少了拉帕替尼在MDA-MB-468细胞中诱导的凋亡。此外，拉帕替尼增加了PP2A活性（与CIP2A抑制有关）。而且，PP2A拮抗剂冈田酸减弱了拉帕替尼诱导的凋亡和p-Akt下调。此外，拉帕替尼通过干扰Elk1与CIP2A启动子的结合间接降低CIP2A转录。重要的是，拉帕替尼在携带MDA-MB-468异种移植瘤的小鼠中显示出抗肿瘤活性，并在这些异种移植瘤中抑制CIP2A以及p-Akt。总之，抑制CIP2A决定了拉帕替尼在TNBC细胞中诱导凋亡的作用。除了作为HER2和EGFR的双靶点酪氨酸激酶抑制剂外，拉帕替尼还在TNBC细胞中抑制CIP2A/PP2A/p-Akt信号通路。
