title: Induction of epithelial-mesenchymal transition via activation of epidermal growth factor receptor contributes to sunitinib resistance in human renal cell carcinoma cell lines.
abstract: Sunitinib is widely used for treating renal cell carcinoma (RCC). However, some patients do not respond to treatment with this drug. We aimed to study the association between sunitinib sensitivity and epithelial-mesenchymal transition (EMT) regulation via epidermal growth factor receptor (EGFR) signaling, which is a mechanism of resistance to anticancer drugs. Three RCC cell lines (786-O, ACHN, and Caki-1) were used, and then we evaluated cell viability, EMT regulatory proteins, and signal transduction with sunitinib treatment. Cell viability of 786-O cells was maintained after treatment with sunitinib. After treatment with sunitinib, EGFR phosphorylation increased in 786-O cells, resulting in an increase in the phosphorylation of extracellular signal-regulated kinase, nuclear translocation of β-catenin, and expression of mesenchymal markers. These results suggest that sunitinib induced EMT via activation of EGFR in 786-O cells, but not in ACHN and Caki-1 cells. Caki-1/SN cells, a resistant cell line generated by continuous exposure to sunitinib, displayed increased phosphorylation of EGFR. Cell viability in the presence of sunitinib was decreased by erlotinib, as the selective inhibitor of EGFR, treatment in 786-O and Caki-1/SN cells. Similarly, erlotinib suppressed sunitinib-induced EGFR activation and upregulated mesenchymal markers. Thus, we postulate that resistance to sunitinib in RCC may be associated with EMT caused by activation of EGFR.
authors: Division of Pharmacokinetics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Hyogo, Japan (A.M., T.N., T.H., M.H.); Department of Pharmacy, Kobe University Hospital, Hyogo, Japan (K.Y., T.N., T.H., M.H.); and Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Hyogo, Japan (Y.N., K.T.).
authors: Atsushi
authors: A
authors: Mizumoto
authors: Division of Pharmacokinetics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Hyogo, Japan (A.M., T.N., T.H., M.H.); Department of Pharmacy, Kobe University Hospital, Hyogo, Japan (K.Y., T.N., T.H., M.H.); and Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Hyogo, Japan (Y.N., K.T.) yamakz@med.kobe-u.ac.jp.
authors: Kazuhiro
authors: K
authors: Yamamoto
authors: Division of Pharmacokinetics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Hyogo, Japan (A.M., T.N., T.H., M.H.); Department of Pharmacy, Kobe University Hospital, Hyogo, Japan (K.Y., T.N., T.H., M.H.); and Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Hyogo, Japan (Y.N., K.T.).
authors: Yuko
authors: Y
authors: Nakayama
authors: Division of Pharmacokinetics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Hyogo, Japan (A.M., T.N., T.H., M.H.); Department of Pharmacy, Kobe University Hospital, Hyogo, Japan (K.Y., T.N., T.H., M.H.); and Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Hyogo, Japan (Y.N., K.T.).
authors: Kohji
authors: K
authors: Takara
authors: Division of Pharmacokinetics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Hyogo, Japan (A.M., T.N., T.H., M.H.); Department of Pharmacy, Kobe University Hospital, Hyogo, Japan (K.Y., T.N., T.H., M.H.); and Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Hyogo, Japan (Y.N., K.T.).
authors: Tsutomu
authors: T
authors: Nakagawa
authors: Division of Pharmacokinetics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Hyogo, Japan (A.M., T.N., T.H., M.H.); Department of Pharmacy, Kobe University Hospital, Hyogo, Japan (K.Y., T.N., T.H., M.H.); and Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Hyogo, Japan (Y.N., K.T.).
authors: Takeshi
authors: T
authors: Hirano
authors: Division of Pharmacokinetics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Hyogo, Japan (A.M., T.N., T.H., M.H.); Department of Pharmacy, Kobe University Hospital, Hyogo, Japan (K.Y., T.N., T.H., M.H.); and Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Hyogo, Japan (Y.N., K.T.).
authors: Midori
authors: M
authors: Hirai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D066246:ErbB Receptors; D000077210:Sunitinib