Snail-Induced Epithelial-to-Mesenchymal Transition Enhances P-gp-Mediated Multidrug Resistance in HCC827 Cells.
Overexpression and activation of P-glycoprotein (P-gp), which mediates efflux transport of various anticancer drugs in cancer cells, is associated with multidrug resistance (MDR). On the other hand, malignant cancer cells frequently undergo epithelial-to-mesenchymal transition (EMT), thereby acquiring high migratory mobility and invasive ability. Snail is a transcriptional factor that represses multiple other factors, and its overexpression is a trigger of EMT. Because both P-gp and Snail are involved in malignant evolution of cancer, in this work, we evaluated whether EMT induced by overexpression of Snail influences P-gp expression and activity. Snail-overexpressing cells showed downregulation of epithelial markers, E-cadherin, occludin, and claudin-1, and upregulation of mesenchymal markers, vimentin and ZEB1. Although Western blot analysis showed that P-gp expression levels were similar in Mock and Snail-overexpressing cells, the results of P-gp functional assays with P-gp substrates rhodamine123 and paclitaxel indicated that P-gp is activated in Snail-overexpressing cells. Indeed, Snail-overexpressing cells showed greater viability than Mock cells in the presence of paclitaxel. We observed caveolin-1 dephosphorylation and decreased growth factor receptor-bound protein 2 (GRB2) expression in Snail-overexpressing cells. These findings suggest a novel pathway leading to cancer MDR, in which Snail induces EMT concomitantly with a decrease in GRB2-mediated caveolin-1 phosphorylation, resulting in activation of P-gp.
Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi, Gunma 370-0033, Japan. Electronic address: 1420101@takasaki-u.ac.jp.
Takumi
T
Tomono
Laboratory of Biopharmaceutics, Department of Pharmacology, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi, Gunma 370-0033, Japan.
Kentaro
K
Yano
Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi, Gunma 370-0033, Japan.
Takuo
T
Ogihara
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D015415:Biomarkers / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D015536:Down-Regulation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D061848:Optical Imaging / Q000379:methods; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D015415:Biomarkers; D051242:Caveolin 1; D005456:Fluorescent Dyes; D014157:Transcription Factors
P-glycoprotein; cancer; cancer chemotherapy; drug resistance; efflux pumps; membrane transporter; multidrug resistance transporters