Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to radiation
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Shao-Qian Sun1,*, Xiaobin Gu1,*, Xian-Shu Gao1, Yi Li 2, Hongliang Yu3, Wei Xiong4, Hao Yu1, Wen Wang1, Yingbo Li2, Yingqi Teng5, Demin Zhou2
1Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, China
2State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
3Department of Radiation Oncology, Jiangsu Cancer Hospital Affiliated with Nanjing Medical University, Nanjing, China
4Tangshan People’s Hospital, Hebei, China
5Beijing Reciproca Pharmaceutical Co. Ltd., Beijing, China
*These authors contributed equally to this work
Xian-Shu Gao, email: [email protected]
Keywords: AKR1C3, radioresistance, ROS, prostaglandinF2α, MAPK
Received: March 28, 2016 Accepted: June 09, 2016 Published: June 30, 2016
Aldo-keto reductase 1C3(AKR1C3) is an enzyme involved in prostaglandins metabolism. Studies suggest that AKR1C3 has a pivotal role in the radioresistance of esophageal cancer and non-small-cell lung cancer, yet the role of AKR1C3 in prostate cancer cells radiation resistance has not yet been clarified. In our study, we established a stable overexpressing AKR1C3 cell line (AKR1C3-over) derived from the prostate cell line DU145 and its control cell line (Control). We conducted colony formation assay to determine the role of AKR1C3 in radioresistance and we used its chemical inhibitor to detect whether it can restored the sensitivity of the acquired tumor cells. Flow cytometry assay was carried out to detect IR-induced ROS accumulation. Elisa was adopted to dedect the concentration of PGF2α in the suspension of the cells after 6GY radiation. Western blotting was used to dedect the MAPK and PPAR γ. The results demonstrated that overexpression of AKR1C3 in prostate cancer can result in radioresistance and suppression of AKR1C3 via its chemical inhibitor indocin restored the sensitivity of the acquired tumor cells. According to the flow cytometry assay, ROS was decreased by 80% in DU145-over cells. Also overexpression of AKR1C3 could result in the accumulation of prostaglandin F2α (PGF2α), which can not only promote prostate cancer cell ’s proliferation but also could enhance prostate cancer cells resistance to radiation and activated the MAPK pathway and inhibited the expression of PPARγ. In conclusion, we found that overexpression of AKR1C3 significantly enhanced human prostate cancer cells resistance to radiation through activation of MAPK pathway.
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