Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to radiation.
Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to radiation.
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AKR1C3的过度表达显着增强人类前列腺癌细胞对辐射的抵抗力
DOI：
10.18632/oncotarget.10347
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发表时间：
2016-07-26
期刊：
影响因子：
--
通讯作者：
Zhou D
中科院分区：
文献类型：
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作者：
Sun SQ;Gu X;Gao XS;Li Y;Yu H;Xiong W;Yu H;Wang W;Li Y;Teng Y;Zhou D
醛酮还原酶1C 3（AKR 1C 3）是一种参与拟南芥素代谢的酶。研究表明AKR 1C 3在食管癌和非小细胞肺癌的放射抵抗中具有关键作用，但AKR 1C 3在前列腺癌细胞放射抵抗中的作用尚未阐明。在我们的研究中，我们建立了一个稳定的过表达AKR 1C 3细胞系（AKR 1C 3-over），来自前列腺细胞系DU 145及其对照细胞系（Control）。我们通过克隆形成实验来确定AKR 1C 3在放射抗性中的作用，并使用其化学抑制剂来检测它是否可以恢复获得性肿瘤细胞的敏感性。流式细胞术检测IR诱导的ROS积累。采用ELISA法检测6 Gy照射后细胞悬液中PGF 2 α的浓度。Western blotting检测MAPK和PPAR γ的表达。结果表明，AKR 1C 3在前列腺癌中的过表达可以导致放射抗性，并且通过其化学抑制剂indocin抑制AKR 1C 3恢复了获得性肿瘤细胞的敏感性。根据流式细胞术测定，在DU 145-over细胞中ROS减少了80%。AKR 1C 3过表达可导致前列腺素F2α（PGF 2 α）的积累，PGF 2 α不仅能促进前列腺癌细胞的增殖，还能增强前列腺癌细胞的放射抵抗力，激活MAPK通路，抑制PPARγ的表达。总之，我们发现AKR 1C 3的过表达通过激活MAPK通路显著增强人前列腺癌细胞的辐射抗性。
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.