title: Tephrosin induces internalization and degradation of EGFR and ErbB2 in HT-29 human colon cancer cells.
abstract: Inactivation of epidermal growth factor receptor (EGFR) family members are prime targets for cancer therapy. Here, we show that tephrosin, a natural rotenoid which has potent antitumor activities, induced internalization of EGFR and ErbB2, and thereby induced degradation of the receptors. Treatment of HT-29 cells with tephrosin inhibited both the ligand-induced and constitutive phosphorylation of EGFR, ErbB2 and ErbB3, and concomitantly suppressed the activation of the downstream signaling molecules such as Akt and Erk1/2 mitogen-activated protein kinase (MAPK). Tephrosin caused internalization of EGFR and ErbB2 into vehicles, which resulted in degradation of the receptors. This degradation was blocked by the lysosomal inhibitor, chloroquine. We also showed that tephrosin induced apoptosis. Tephrosin did not induce the proteolytic processing of caspase-3 and poly(ADP-ribose) polymerase (PARP), but did nuclear translocation of apoptosis-inducing factor (AIF), suggesting that tephrosin may induce caspase-independent apoptosis. These findings provide the first evidence that tephrosin could exert antitumor effects by inducing internalization and degradation of inactivated EGFR and ErbB2 in human colon cancer cells.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Sujin
authors.initials: S
authors.lastname: Choi
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Choi
authors.forename: Nguyen Tien
authors.initials: NT
authors.lastname: Dat
authors.forename: Cheol
authors.initials: C
authors.lastname: Hwangbo
authors.forename: Jung Joon
authors.initials: JJ
authors.lastname: Lee
authors.forename: Jeong-Hyung
authors.initials: JH
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D012402:Rotenone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D020169:Caspases; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D012402:Rotenone; C087230:heregulin beta1; C480848:tephrosin