Huang, Wei-ChienWei-ChienHuangHuang, Wei-Pang et al.Wei-Pang et al.Huang2012-10-192018-07-062012-10-192018-07-06201100219258http://ntur.lib.ntu.edu.tw//handle/246246/242956http://ntur.lib.ntu.edu.tw/bitstream/246246/242956/-1/60.pdfhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-79957982003&doi=10.1074%2fjbc.M111.240796&partnerID=40&md5=ad703f77d368995fae664ac4d04df487Epidermal 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. ? 2011 by The American Society for Biochemistry and Molecular Biology, Inc.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. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.en-US[SDGs]SDG3Acquired resistance; Cancer cells; Cancer progression; Cancer therapy; Clinical efficacy; Epidermal growth factor receptors; Erlotinib; Gefitinib; Gene transcriptions; Kinase inhibitors; Molecular mechanism; Non small cell lung cancer; Nuclear translocations; Protein expressions; Receptor-tyrosine kinase; Tyrosine kinase inhibitor; Wild types; Amino acids; Cells; Enzymes; Genes; Peptides; Phosphorylation; Transcription; Diseases; breast cancer resistance protein; epidermal growth factor receptor; gefitinib; protein kinase B; article; cancer cell culture; cancer resistance; cell nucleus; controlled study; drug mechanism; drug sensitivity; genetic transcription; priority journal; promoter region; protein expression; protein function; protein phosphorylation; protein targeting; protein transport; signal transduction; wild type; Active Transport, Cell Nucleus; Antineoplastic Agents; ATP-Binding Cassette Transporters; Breast Neoplasms; Cell Line, Tumor; Cell Nucleus; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Proteins; Phosphorylation; Proto-Oncogene Proteins c-akt; Quinazolines; Receptor, Epidermal Growth Factorjournal article10.1074/jbc.M111.24079510.1074/jbc.M111.240796214870202-s2.0-79957982003http://ntur.lib.ntu.edu.tw/bitstream/246246/242956/-1/60.pdf