Cardiac glycosides inhibit cancer through Na/K-ATPase-dependent cell death induction.
Cardiac glycosides inhibit cancer through Na/K-ATPase-dependent cell death induction.
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强心苷通过 Na/K-ATP 酶依赖性细胞死亡诱导抑制癌症
DOI：
10.1016/j.bcp.2020.114226
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发表时间：
2020-12
影响因子：
5.8
通讯作者：
Tang, Jinshan
中科院分区：
文献类型：
--
作者：
Geng, Xinran;Wang, Fangfang;Tian, Danmei;Huang, Lihua;Streator, Evan;Zhu, Jingjing;Kurihara, Hiroshi;He, Rongrong;Yao, Xinsheng;Zhang, Youwei;Tang, Jinshan
成功的药物再利用依赖于对目标化合物分子机制的理解。强心苷类化合物具有较强的抗肿瘤活性，但其抗肿瘤作用的药理机制尚不清楚，限制了其在肿瘤治疗中的进一步发展。一个瓶颈是缺乏对药物治疗早期改变的基因和信号通路的全面了解，这是了解它们如何抑制癌症的关键。为了解决这个问题，我们首先研究了一组68种天然分离的强心苷的抗癌作用。我们的研究结果说明了这些化合物对癌细胞存活的关键结构活性关系。我们证实了强心苷在小鼠肿瘤移植瘤中的抗癌作用。通过RNA测序，定量PCR和免疫印迹，我们发现，强心苷首先激活自噬，然后诱导凋亡。通过雷帕霉素进一步激活自噬或通过半胱天冬酶抑制剂抑制凋亡减轻了心脏糖苷诱导的细胞死亡，而通过RNA干扰介导的关键自噬基因的耗竭抑制自噬增强了细胞死亡。虽然通过RNA干扰耗尽强心苷的蛋白靶Na/K-ATP酶抑制了强心苷的自噬激活和凋亡诱导，但人而非啮齿动物Na/K-ATP酶的表达增加了细胞对强心苷的敏感性。总之，我们的分析揭示了强心苷治疗早期自噬和凋亡的顺序激活，并表明Na/K-ATP酶在其抗癌作用中的重要性。
Successful drug repurposing relies on the understanding of molecular mechanisms of the target compound. Cardiac glycosides have demonstrated potent anticancer activities; however, the pharmacological mechanisms underlying their anticancer effects remained elusive, which has restricted their further development in cancer treatment. A bottleneck is the lack of comprehensive understanding about genes and signaling pathways that are altered at the early stage of drug treatment, which is key to understand how they inhibit cancer. To address this issue, we first investigated the anticancer effects of a panel of 68 naturally isolated cardiac glycosides. Our results illustrate critical structure activity relationship of these compounds on cancer cell survival. We confirmed the anticancer effect of cardiac glycoside in mouse tumor xenografts. Through RNA sequencing, quantitative PCR and immunoblotting, we show that cardiac glycoside first activated autophagy and then induced apoptosis. Further activating autophagy by rapamycin or inhibiting apoptosis by caspase inhibitor mitigated cardiac glycoside-induced cell death, whereas inhibiting autophagy by RNA interference-mediated depletion of critical autophagy genes enhanced cell death. While depletion of Na/K-ATPase, the protein target of cardiac glycosides, by RNA interference inhibited both autophagy activation and apoptosis induction by cardiac glycoside, expression of human, but not rodent Na/K-ATPase, increased cell sensitivity to cardiac glycoside. In conclusion, our analyses reveal sequential activation of autophagy and apoptosis during early stages of cardiac glycoside treatment and indicate the importance of Na/K-ATPase in their anticancer effects.
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影响因子：
3.8
作者：
Elbaz, Hosam A.;Stueckle, Todd A.;Wang, Hua-Yu Leo;O'Doherty, George A.;Lowry, David T.;Sargent, Linda M.;Wang, Liying;Dinu, Cerasela Zoica;Rojanasakul, Yon
通讯作者：
Rojanasakul, Yon
影响因子：
19
作者：
Funderburk SF;Wang QJ;Yue Z
通讯作者：
Yue Z
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
11.2
作者：
Frese, S;Frese-Schaper, M;Schmid, RA
通讯作者：
Schmid, RA
影响因子：
1.7
作者：
Cheng, Huo-Yun;Tian, Dan-Mei;Yao, Xin-Sheng
通讯作者：
Yao, Xin-Sheng