title: ERBB3 knockdown induces cell cycle arrest and activation of Bak and Bax-dependent apoptosis in colon cancer cells.
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.
authors: Department of Life Science Ewha Womans University, Seoul, S. Korea.
authors: Hyunji
authors: H
authors: Lee
authors: Department of Life Science Ewha Womans University, Seoul, S. Korea.
authors: Hyunjung
authors: H
authors: Lee
authors: Department of Life Science Ewha Womans University, Seoul, S. Korea.
authors: Hyunjung
authors: H
authors: Chin
authors: Department of Life Science Ewha Womans University, Seoul, S. Korea.
authors: Kyoungmi
authors: K
authors: Kim
authors: Department of Life Science Ewha Womans University, Seoul, S. Korea. GT5 program, Ewha Womans University, Seoul, S. Korea.
authors: Daekee
authors: D
authors: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020893:Receptor, ErbB-3 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020893:Receptor, ErbB-3; D058570:TOR Serine-Threonine Kinases; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C494772:BAK1 protein, human; C494826:BAX protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C581292:ERBB3 protein, human