Liu Zhenyu, Shi Aiping, Song Dong, Han Bing, Zhang Zhiru, Ma Le, Liu Dongxu, Fan Zhimin
Department of Breast Surgery, The First Hospital of Jilin University Changchun, Jilin Province, China.
School of Science, Auckland University of Technology Auckland, New Zealand.
Am J Cancer Res. 2017 Mar 1;7(3):574-583. eCollection 2017.
Clear evidence has linked obesity to a high risk of incidence as well as poor clinical outcome of breast cancer. It has been proven that changes in the levels of adipokines caused by obesity are associated with the initiation and progression of breast cancer. Resistin is a novel adipokine that is upregulated in breast cancer patients and promotes breast cancer cell growth, invasion, and migration. The aim of the study was to investigate whether resistin affected the efficacy of doxorubicin (Dox), one of the most effective anthracycline chemotherapeutic agents in the treatment of breast cancer. Treatment with resistin significantly attenuated Dox-induced apoptosis in a dose- and time-dependent manner, resulting in an increase in breast cancer cells survival. Moreover, resistin significantly induced autophagy flux and inhibition of autophagy abrogated the pro-survival effect of resistin in doxorubicin-treated cells. Furthermore, the AMPK/mTOR/ULK1 and JNK signaling pathways were activated by resistin treatment. Inhibition of these two pathways markedly reduced the ratio of LC3B-II/LC3B-I and increased cell apoptosis induced by Dox. For the first time, our findings indicate that resistin confers resistance to doxorubicin-induced apoptosis through autophagy induction and that this process involves the activation of AMPK/mTOR/ULK1 and JNK signaling pathways. Our findings suggest that resistin antagonism may be a novel strategy to overcome resistance to doxorubicin-based chemotherapy in breast cancer patients.
确凿证据表明，肥胖与乳腺癌的高发病风险以及不良临床结局相关。已证实，肥胖引起的脂肪因子水平变化与乳腺癌的发生和发展有关。抵抗素是一种新型脂肪因子，在乳腺癌患者中上调，并促进乳腺癌细胞的生长、侵袭和迁移。本研究的目的是调查抵抗素是否会影响阿霉素（Dox）的疗效，阿霉素是治疗乳腺癌最有效的蒽环类化疗药物之一。抵抗素处理以剂量和时间依赖性方式显著减弱了阿霉素诱导的细胞凋亡，导致乳腺癌细胞存活率增加。此外，抵抗素显著诱导自噬通量，抑制自噬消除了抵抗素在阿霉素处理细胞中的促存活作用。此外，抵抗素处理激活了AMPK/mTOR/ULK1和JNK信号通路。抑制这两条通路显著降低了LC3B-II/LC3B-I的比率，并增加了阿霉素诱导的细胞凋亡。我们的研究结果首次表明，抵抗素通过诱导自噬赋予对阿霉素诱导凋亡的抗性，并且这一过程涉及AMPK/mTOR/ULK1和JNK信号通路的激活。我们的研究结果表明，抵抗素拮抗作用可能是克服乳腺癌患者对基于阿霉素化疗耐药的一种新策略。
