Int J Med Sci 2014; 11(11):1089-1097. doi:10.7150/ijms.9239

Research Paper

AKR1C3 Overexpression Mediates Methotrexate Resistance in Choriocarcinoma Cells

Jing Zhao1, Yang Xiang1✉, Changji Xiao1, Peng Guo1, Dan Wang1, Ying Liu1, Yun Shen2

1. Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
2. Reproductive Health Centre, National Science Institute for Family Planning, Beijing, People's Republic of China.

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Zhao J, Xiang Y, Xiao C, Guo P, Wang D, Liu Y, Shen Y. AKR1C3 Overexpression Mediates Methotrexate Resistance in Choriocarcinoma Cells. Int J Med Sci 2014; 11(11):1089-1097. doi:10.7150/ijms.9239. Available from

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Background: Chemotherapy is typically used to treat choriocarcinoma, but a small proportion of tumors develop resistance to chemotherapy. Similarly, methotrexate (MTX) is a first-line chemotherapy used to treat choriocarcinoma; although ~30% of patients are drug-resistant for MTX mono-therapy. Thus, we sought to elucidate the mechanism of chemotherapeutic-resistance of MTX.

Methods: RNA interference technology, colony formation, and MTT assays were used to investigate the role of aldo-keto reductase family 1, member C3 (AKR1C3) in MTX resistance in choriocarcinoma cells.

Results: AKR1C3 expression was higher in JeG-3R cells compared to JeG-3 cells and targeted inhibition of AKR1C3 expression with shRNA suppresses growth of choriocarcinoma cells as measured by colony formation and MTT assays. Overexpression of AKR1C3 increased chemotherapeutic resistance in JeG-3 cells. Furthermore, AKR1C3 silencing increases sensitivity to MTX in JeG-3R choriocarcinoma cells. Increasing MTX sensitivity spears to be related to DNA damage induction by increased reactive oxygen species (ROS), apoptosis, and cell cycle arrest.

Conclusions: Data show that AKR1C3 is critical to the development of methotrexate resistance in choriocarcinoma and suggest that AKR1C3 may potentially serve as a therapeutic marker for this disease.

Keywords: AKR1C3, Methotrexate (MTX), Choriocarcinoma cells, ROS, Chemotherapeutic-resistance.