Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1α.
Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1α.
复制标题
小檗碱通过抑制 AMPK-HIF-1 α 逆转缺氧诱导的乳腺癌化疗耐药性
DOI：
10.7150/ijbs.18969
复制
发表时间：
2017
影响因子：
9.2
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Pan Y;Shao D;Zhao Y;Zhang F;Zheng X;Tan Y;He K;Li J;Chen L
乳腺癌是最常见的癌症类型，也是美国女性癌症死亡的第二大原因。化疗耐药性是常见的，在一段可变的时间后是不可避免的。因此，化疗增敏是治疗耐药乳腺癌的必要策略。本研究采用低氧培养MCF-7乳腺癌细胞一周，诱导MCF-7乳腺癌细胞对阿霉素（DOX）产生耐药性。观察不同剂量的中药小檗碱对MFC-7/缺氧细胞对阿霉素敏感性的影响。我们发现缺氧增加乳腺癌细胞对DOX的抗性，并激活AMPK。小剂量小檗碱可使MCF-7/缺氧细胞对阿霉素的化疗敏感性恢复，而大剂量小檗碱可直接诱导MCF-7/缺氧细胞凋亡。小檗碱低剂量和高剂量均可下调AMPK和HIF-1α的蛋白表达。但HIF-1α下游发生了依赖于小檗碱剂量的分叉：AMPK-HIF-1α-P-gp失活对低剂量小檗碱的DOX化疗敏感性起关键作用，而AMPK-HIF-1α下调诱导p53激活导致高剂量小檗碱的细胞凋亡。这一结果与小檗碱联合阿霉素或单独大剂量小檗碱治疗的MCF-7耐药移植瘤小鼠模型一致。这项工作揭示了克服耐药乳腺癌的潜在治疗尝试。
Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. Chemoresistance is common and inevitable after a variable period of time. Therefore, chemosensitization is a necessary strategy on drug-resistant breast cancer. In this study, MCF-7 breast cancer cell was cultured under hypoxia for a week to induce the resistance to doxorubincin (DOX). The effect of different doses of berberine, a traditional Chinese medicine, on DOX sensitivity to MFC-7/hypoxia cells was observed. We found that hypoxia increased DOX resistance on breast cancer cells with the AMPK activation. Low-dose berberine could resensitize DOX chemosensitivity in MCF-7/hypoxia cell, however, high-dose berberine directly induced apoptosis. The intriguing fact was that the protein expressions of AMPK and HIF-1α were down-regulated by berberine, either low dose or high dose. But the downstream of HIF-1α occurred the bifurcation dependent on the dosage of berberine: AMPK-HIF-1α-P-gp inactivation played a crucial role on the DOX chemosensitivity of low-dose berberine, while AMPK-HIF-1α downregulaton inducing p53 activation led to apoptosis in high-dose berberine. These results were consistent to the transplanted mice model bearing MCF-7 drug-resistance tumor treated by berberine combined with DOX or high-dose berberine alone. This work shed light on a potentially therapeutic attempt to overcome drug-resistant breast cancer.