Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan; Taipei Medical University Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Nutrition Research Center, Taipei Medical University Hospital, Taipei, Taiwan; Taipei Medical University and Affiliated Hospitals Pancreatic Cancer Groups, Taipei Cancer Center, Taipei Medical University, Taiwan.
Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei, Taiwan; Taipei Medical University Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
Biomed Pharmacother. 2022 Sep;153:113520. doi: 10.1016/j.biopha.2022.113520. Epub 2022 Aug 15.
Oxaliplatin, a third-generation platinum derivative, has become one of the main chemotherapeutic treatments for esophagus, gastric and colorectal cancer; however, it is still unclear the potential effectiveness for pancreatic ductal adenocarcinoma (PDAC) with gemcitabine resistance. Here, we observed that PDAC tumors have low level of organic cation transporter 2 (OCT2, also known as SLC22A2) compared with non-tumor tissues and identified that OCT2 expression is positively correlated with oxaliplatin sensitivity in PDAC cells. Treatment of OCT2 inhibitors or knockdown of OCT2 expression significantly decreased the sensitivity to oxaliplatin in PANC-1 cells. In addition, bisulfite sequencing polymerase chain reaction analysis revealed that higher methylation frequency represses OCT2 expression in gemcitabine-resistant PANC-1 (PANC-1/GR) cells. Moreover, we found that treatment of DNA methyltransferase (DNMT) inhibitors, decitabine or 5-azacytidine recover OCT2 expression and oxaliplatin sensitivity in PANC-1/GR cells, and DNMT1 level has inverse correlation with OCT2 expression in PDAC cells and tumors. Our findings jointly suggest that OCT2 expression is a potential and predictive marker for evaluating oxaliplatin sensitivity and developing alternative treatments for PDAC patients with gemcitabine resistance.
奥沙利铂是第三代铂类衍生物，已成为治疗食管癌、胃癌和结直肠癌的主要化疗药物之一；然而，对于吉西他滨耐药的胰腺导管腺癌（PDAC），其潜在疗效仍不清楚。在这里，我们观察到与非肿瘤组织相比，PDAC 肿瘤中有机阳离子转运蛋白 2（OCT2，也称为 SLC22A2）水平较低，并确定 OCT2 表达与 PDAC 细胞对奥沙利铂的敏感性呈正相关。OCT2 抑制剂的处理或 OCT2 表达的敲低显著降低了 PANC-1 细胞对奥沙利铂的敏感性。此外，亚硫酸氢盐测序聚合酶链反应分析显示，较高的甲基化频率抑制了吉西他滨耐药的 PANC-1（PANC-1/GR）细胞中的 OCT2 表达。此外，我们发现 DNA 甲基转移酶（DNMT）抑制剂地西他滨或 5-氮杂胞苷处理可恢复 PANC-1/GR 细胞中 OCT2 表达和奥沙利铂敏感性，并且 PDAC 细胞和肿瘤中的 DNMT1 水平与 OCT2 表达呈负相关。我们的研究结果共同表明，OCT2 表达是评估奥沙利铂敏感性和为吉西他滨耐药的 PDAC 患者开发替代治疗方法的潜在预测标志物。
