Abstract 3119: Phosphorylation of epidermal growth factor receptor at Ser1046/1047 by p38 mitogen-activated protein kinase plays a critical role in its downregulation in cancer cells

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Abstract The mechanism underlying downregulation of EGF receptor (EGFR) is important for the regulation of cancer cells. Although the phosphorylation of EGFR at Tyr1045 and Ser1046/1047 reportedly account for its downregulation, the exact mechanism remains unclear. We recently reported that p38 mitogen-activated protein kinase (MAPK), a stress-inducible kinase believed to negatively regulate tumorigenesis, controls EGFR downregulation via its phosphorylation at Ser1046/1047 (Cancer Lett 2009;277:108-13). To further investigate the role of phosphorylation of p38 MAPK in the action of anti-cancer drug, we examined the effects of (−)-epigallocatechin gallate (EGCG) and several HSP90 inhibitors (17-AAG, geldanamycin and 17-DMAG) on p38 MAPK in colon and pancreatic cancer cells. While EGCG and HSP90 inhibitors caused downregulation of EGFR and subsequent cell death, they induced phosphorylation of p38 MAPK, and inhibition of p38 MAPK suppressed the internalization and subsequent degradation of EGFR. Moreover, we found that they caused phosphorylation of EGFR at Ser1046/1047, not Tyr1045, and that they were also suppressed by the inhibition of p38 MAPK. Taken together, our results strongly suggest that phosphorylation of EGFR at Ser 1046/1047 via activation of p38 MAPK plays a pivotal role in anti-cancer drug-induced downregulation of EGFR. These findings may indicate new therapeutic strategies for inhibiting the proliferation of human cancers that are highly dependent on the activation of EGFR. (Adachi S et al., Carcinogenesis 2009;30:1544-52) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3119.