Organic cation transporter 6 directly confers resistance to anticancer platinum drugs
Organic cation transporter 6 directly confers resistance to anticancer platinum drugs
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DOI：
10.3892/br.2016.772
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发表时间：
2016-11-01
影响因子：
2.3
通讯作者：
Niimi, Akio
中科院分区：
文献类型：
--
作者：
Oguri, Tetsuya;Kunii, Eiji;Niimi, Akio
溶质载体家族的有机阳离子转运体(OCTs)在细胞摄取抗癌铂类药物中起着至关重要的作用。最近，我们发现OCT6表达降低与顺铂(CDDP)细胞内摄取减少相关，并伴随着对CDDP的耐药。在目前的研究中，我们研究了OCT是否直接导致对另一种铂类药物奥沙利铂(L-OHP)的耐药性。为了解决这个问题，我们使用亲本肺癌细胞系PC-14和SBC3，耐L-OHP的亚系PC-14/L-OHP和SBC3/L-OHP，以及一个耐顺铂的亚系PC-14/CDDP，来检测OCT的表达与细胞内铂药物浓度或铂耐药的关系。两个L-OHP抗性亚系对顺铂和L-OHP表现交叉耐药，OCT6表达降低。与亲代细胞相比，PC-14/L-OHP细胞内L-OHP的积聚减少。研究结果表明，OCT6表达的降低通过减少对铂类药物的摄取，使亚系对铂类药物产生耐药性。利用高表达OCT6的PC-14/CDDP细胞系，我们证实与亲本细胞系相比，细胞内L-OHP的浓度随着OCT6的过表达而增加。此外，OCT6在肺癌和结肠癌组织的筛查小组以及匹配的正常对照组织中都有表达。综上所述，目前的研究结果表明，OCT6通过介导癌细胞对铂类药物的摄取，直接参与了铂类药物的耐药。
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.