期刊
ONCOTARGET
卷 5, 期 13, 页码 5138-5152出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2094
关键词
ERBB3 targeting; Cell cycle arrest; Apoptosis; Bak; Bax
资金
- National Research Foundation of Korea from Korea Government [2011-0009719, 2012M3A9C5048707]
- National Research Foundation of Korea [2012M3A9C5048707, 2011-0009719] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
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