Nuclear translocation of epidermal growth factor receptor by Akt-dependent phosphorylation enhances breast cancer-resistant protein expression in gefitinib-resistant cells

Wei Chien Huang, Yun Ju Chen, Long Yuan Li, Ya Ling Wei, Sheng Chieh Hsu, Shing Ling Tsai, Pei Chun Chiu, Wei Pang Huang, Ying Nai Wang, Chung Hsuan Chen, Wei Chao Chang, Wen Chang Chang, Andy Jer En Chen, Chang Hai Tsai, Mien Chie Hung

研究成果: 雜誌貢獻文章同行評審

130 引文 斯高帕斯(Scopus)

摘要

Epidermal growth factor receptor (EGFR), an aberrantly overexpressed or activated receptor-tyrosine kinase in many cancers, plays a pivotal role in cancer progression and has been an attractive target for cancer therapy. Gefitinib and erlotinib, two EGFR-tyrosine kinase inhibitors, have been approved for nonsmall cell lung cancer. However, durable clinical efficacy of these EGFR inhibitors is severely limited by the emergence of acquired resistance. For example, the expression of breast cancer-resistant protein (BCRP/ABCG2) has been shown to confer acquired resistance of wild-type EGFR (wtEGFR)-expressing cancer cells to gefitinib. However, the underlying molecular mechanisms still remain unclear. Here, we show that wtEGFR expression is elevated in the nucleus of acquired gefitinib-resistant cancer cells. Moreover, nuclear translocation of EGFR requires phosphorylation at Ser-229 by Akt. In the nucleus, EGFR then targets the proximal promoter of BCRP/ABCG2 and thereby enhances its gene transcription. The nuclear EGFR-mediated BCRP/ABCG2 expression may contribute at least in part to the acquired resistance of wtEGFR-expressing cancer cells to gefitinib. Our findings shed light on the role of nuclear EGFR in the sensitivity of wtEGFR-expressing cancer cells to EGFR tyrosine kinase inhibitors and also deciphered a putative molecular mechanism contributing to gefitinib resistance through BCRP/ ABCG2 expression.

原文英語
頁(從 - 到)20558-20568
頁數11
期刊Journal of Biological Chemistry
286
發行號23
DOIs
出版狀態已發佈 - 6月 10 2011
對外發佈

ASJC Scopus subject areas

  • 生物化學
  • 細胞生物學
  • 分子生物學

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