Organic cation transporter 2 activation enhances sensitivity to oxaliplatin in human pancreatic ductal adenocarcinoma

Ching Feng Chiu, Ji Min Park, Hsin Hua Chen, Chen Zou Mau, Pai Sheng Chen, Yen Hao Su, Hsin An Chen, Yun Ru Liu, Tsung Han Hsieh, Chien Chao Chiu, Shao Wen Hung, Cheng Yi Kuo, Young Mao Chen, Chi Fen Chang

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number113520
JournalBiomedicine and Pharmacotherapy
Volume153
DOIs
Publication statusPublished - Sept 2022

Keywords

  • DNA methyltransferase
  • Gemcitabine
  • Organic cation transporter 2
  • Oxaliplatin
  • Pancreatic ductal adenocarcinoma

ASJC Scopus subject areas

  • Pharmacology

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