ERBB3 knockdown induces cell cycle arrest and activation of Bak and Bax-dependent apoptosis in colon cancer cells

Hyunji Lee, Hyunjung Lee, Hyunjung Chin, Kyoungmi Kim, Daekee Lee

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5138-5152
Number of pages15
JournalOncotarget
Volume5
Issue number13
DOIs
Publication statusPublished - 2014 Jan 1
Externally publishedYes

Fingerprint

Cell Cycle Checkpoints
Colonic Neoplasms
Phosphatidylinositol 3-Kinases
Apoptosis
Apoptosis Regulatory Proteins
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Up-Regulation
Down-Regulation
Mutation
Therapeutics
Neoplasms

Keywords

  • Apoptosis
  • Bak
  • Bax
  • Cell cycle arrest
  • ERBB3 targeting

ASJC Scopus subject areas

  • Oncology

Cite this

ERBB3 knockdown induces cell cycle arrest and activation of Bak and Bax-dependent apoptosis in colon cancer cells. / Lee, Hyunji; Lee, Hyunjung; Chin, Hyunjung; Kim, Kyoungmi; Lee, Daekee.

In: Oncotarget, Vol. 5, No. 13, 01.01.2014, p. 5138-5152.

Research output: Contribution to journalArticle

Lee, Hyunji ; Lee, Hyunjung ; Chin, Hyunjung ; Kim, Kyoungmi ; Lee, Daekee. / ERBB3 knockdown induces cell cycle arrest and activation of Bak and Bax-dependent apoptosis in colon cancer cells. In: Oncotarget. 2014 ; Vol. 5, No. 13. pp. 5138-5152.
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