Lee Hyunji, Lee Hyunjung, Chin Hyunjung, Kim Kyoungmi, Lee Daekee
Department of Life Science Ewha Womans University, Seoul, S. Korea.
Department of Life Science Ewha Womans University, Seoul, S. Korea. GT5 program, Ewha Womans University, Seoul, S. Korea.
Oncotarget. 2014 Jul 15;5(13):5138-52. doi: 10.18632/oncotarget.2094.
ERBB3 is an emerging target for cancer therapy among the EGFR family. Contrary to resistance against EGFR and ERBB2 targeting, the genetic inhibition of ERBB3 results in anti-tumorigenic in HCT116 colon cancer cells harboring constitutively active KRAS and PIK3CA mutations. Still, the anti-tumorigenic molecular mechanism has not been defined. We demonstrated in this study that ERBB3 knockdown resulted in cell cycle arrest and activation of Bak and Bax-dependent apoptosis. Apoptosis was irrelevant to the majority of BH3-only pro-apoptotic proteins and correlated with the transcriptional upregulation of Bak and p53-dependent Bax translocation. Treatment with LY294002, a PI3K inhibitor, resulted in cell cycle arrest without apoptosis and a concomitant down-regulation of cap-dependent translation by the suppression of the PI3K/AKT/mTOR pathway. However, the inhibition of cap-dependent translation by ERBB3 knockdown occurred without altering the PI3K/AKT/mTOR pathway. In addition, ERBB3 knockdown-induced cell cycle arrest was observed in most colon cancer cells but was accompanied by apoptosis in p53 wild-type cells. These results indicate that ERBB3 is a potential target for EGFR- and ERBB2-resistant colon cancer therapy.
ERBB3是表皮生长因子受体（EGFR）家族中一个新兴的癌症治疗靶点。与针对EGFR和ERBB2靶向治疗的耐药性相反，对ERBB3进行基因抑制会在携带组成型活性KRAS和PIK3CA突变的HCT116结肠癌细胞中产生抗肿瘤作用。然而，其抗肿瘤分子机制尚未明确。我们在本研究中证明，ERBB3基因敲低导致细胞周期停滞以及Bak和Bax依赖性凋亡的激活。凋亡与大多数仅含BH3结构域的促凋亡蛋白无关，并且与Bak的转录上调以及p53依赖性Bax易位相关。用PI3K抑制剂LY294002处理导致细胞周期停滞但无凋亡，并且通过抑制PI3K/AKT/mTOR途径同时下调帽依赖性翻译。然而，ERBB3基因敲低对帽依赖性翻译的抑制在未改变PI3K/AKT/mTOR途径的情况下发生。此外，在大多数结肠癌细胞中观察到ERBB3基因敲低诱导的细胞周期停滞，但在p53野生型细胞中伴有凋亡。这些结果表明，ERBB3是EGFR和ERBB2耐药性结肠癌治疗的一个潜在靶点。
