title: Organic cation transporter 6 directly confers resistance to anticancer platinum drugs.
abstract: Organic cation transporters (OCTs) of the solute carrier family 22 have a critical role in the cellular uptake of anticancer platinum drugs. Recently, we found that a decreased OCT6 expression is associated with a reduced intracellular uptake of cisplatin (CDDP), and concomitant resistance to CDDP. In the present study, we examined whether OCTs directly confer resistance to another platinum drug, oxaliplatin (L-OHP). To address this, we used parental lung cancer cell lines, PC-14 and SBC3; L-OHP-resistant sublines, PC-14/L-OHP and SBC3/L-OHP; and one CDDP-resistant subline PC-14/CDDP, to examine the relationships between the expression of OCTs and intracellular platinum drug concentration or platinum drug resistance. The two L-OHP-resistant sublines showed cross resistance to CDDP and L-OHP, and a decreased expression of OCT6. The intracellular accumulation of L-OHP in PC-14/L-OHP cells was reduced compared with the parental cells. The findings suggested that a reduced OCT6 expression confers platinum drug resistance in the sublines by decreasing the uptake of platinum drugs. Using the PC-14/CDDP cell line engineered to overexpress OCT6, we confirmed that the intracellular L-OHP concentration was increased concomitantly with OCT6 overexpression compared with the parental cell line. Additionally, OCT6 was expressed in a screening panel of lung and colon cancer tissues and matched normal control tissues. Taken together with the previous results, the present findings indicate that OCT6 is directly involved in platinum drug resistance by mediating platinum drug uptake in cancer cells.
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Oguri
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kunii
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sone
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Uemura
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takakuwa
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kanemitsu
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Ohkubo
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Takemura
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Maeno
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Niimi
keywords: cisplatin; drug resistance; multidrug resistance; organic cation transporter; oxaliplatin; toxin extrusion