Organic cation transporter 3 mediates cisplatin and copper cross-resistance in hepatoma cells
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Sarah Guttmann1,*, Gursimran Chandhok1,2,*, Sara Reinartz Groba1, Christoph Niemietz1, Vanessa Sauer1, Amanda Gomes1,3, Giuliano Ciarimboli4, Uwe Karst5, Andree Zibert1 and Hartmut H. Schmidt1
1Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany
2Present address: Monash Biomedicine Discovery Institute, and Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
3Present address: Wilson Disease Clinic, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
4Universitätsklinikum Münster, Medizinische Klinik D, Experimentelle Nephrologie, Münster, Germany
5Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany
*These authors contributed equally to this work
Hartmut H. Schmidt, email: [email protected]
Keywords: OCT3; ATP7B; MT1; cisplatin; copper cross-resistance
Received: June 30, 2017 Accepted: November 15, 2017 Published: December 12, 2017
Platinum-based drugs are first-line compounds in the treatment of many solid cancers. Major obstacles are tumors that become resistant and toxic side effects, both largely due to the expression of transporters that mediate the cellular processing of platinum. In this study, we addressed the establishment of cisplatin resistance in the absence of copper transporter ATP7B that has been previously found to be overexpressed in various resistant cells. Cisplatin sensitivity, induction of apoptosis, drug accumulation, and transporter gene expression were determined in hepatoma cell lines. Knockout or overexpression of copper transporter ATP7B did not affect cisplatin sensitivity. Cisplatin resistant cells showed a stably reduced cisplatin accumulation and a downregulation of organic cation transporter 3 (OCT3). In contrast, OCT3 overexpression could reverse resistance. Reduced MT1 expression was detected in the resistant cell line, however transient and highly dependent on the presence of cisplatin. Cross-resistance to copper was also associated with OCT3 downregulation. Our results suggest that a decreased level of OCT3 expression results in resistance to cisplatin and copper. OCT3 may represent a novel target for improved prognosis and anticancer therapy, including HCC.
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