醛酮还原酶AKR1C3介导乳腺癌阿霉素耐药的作用及其机制

王凯振; 杨婉婉; 徐晟瑶; 郭青龙; 赵丽

doi:10.11665/j.issn.1000-5048.20210313

醛酮还原酶AKR1C3介导乳腺癌阿霉素耐药的作用及其机制

中国药科大学基础医学与临床药学学院，南京 210009

基金项目: 国家自然科学基金资助项目（No.81830105）

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出版历程
- 收稿日期: 2021-03-04
- 修回日期: 2021-05-12
- 刊出日期: 2021-06-24

Effects and mechanisms of AKR1C3 inducing doxorubicin resistance in breast cancer

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

Funds: This study was supported by the National Natural Science Foundation of China (No.81830105)

摘要

摘要: 为了探讨醛酮还原酶AKR1C3 在乳腺癌阿霉素耐药中的作用，成功建立了阿霉素耐药的人乳腺癌细胞株MCF-7/DOX以及AKR1C3稳定过表达和敲低的乳腺癌细胞株。Western blot发现MCF-7/DOX细胞内AKR1C3的表达水平明显高于敏感株MCF-7细胞。CCK-8细胞药物敏感实验和 DAPI 染色实验发现在AKR1C3高表达的细胞中，阿霉素的细胞毒性明显降低（IC₅₀增加了6倍）；集落形成实验也证实AKR1C3过表达细胞中，集落形成能力增高。进一步实验证实，AKR1C3介导的β-catenin入核增多是导致乳腺癌细胞阿霉素耐药的原因之一。应用β-catenin 抑制剂XAV939，能够逆转AKR1C3诱导的阿霉素耐药。上述结果提示，AKR1C3可以作为逆转阿霉素耐药的潜在治疗靶标。
- 醛酮还原酶 /
- AKR1C3 /
- β-catenin /
- 乳腺癌 /
- 阿霉素耐药
Abstract: To explore the mechanisms by which AKR1C3 induces tumor resistance, human breast cancer cell strain MCF-7/DOX resistant to doxorubicin, MCF-7/ AKR1C3 cells for overexpression of AKR1C3 and MCF-7/DOX-KD cells for knockdown of AKR1C3 in MCF-7/DOX cells were established. Western blot analysis found that AKR1C3 was expressed at a higher level in MCF-7/DOX than MCF-7 wild type cells. Similarly, CCK-8 and DAPI confirmed that MCF-7/ AKR1C3 cells were more resistant to DOX than AKR1C3 wild types as the IC₅₀ was increased 6 times in MCF-7/AKR1C3 cells more than in AKR1C3 wild type cells. Meanwhile, colony formation ability was also enhanced after AKR1C3 was over-expressed in MCF-7 cells.Cytoplasmic/nuclear separation analysis and IF further found that β-catenin nuclear translocation mediated by AKR1C3 was the main reason contributing to the occurrence of DOX-resistant breast cancer cells. β-catenin inhibitor, XAV939, could reverse the AKR1C3 induced doxorubicin resistance in MCF-7 cells.Results indicated that AKR1C3 could be a potential therapeutic target in breast cancer cells.
- aldo-keto reductase /
- AKR1C3 /
- β-catenin /
- breast cancer /
- DOX resistance

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