Atorvastatin preferentially inhibits the growth of high ZEB-expressing canine cancer cells
Atorvastatin preferentially inhibits the growth of high ZEB-expressing canine cancer cells
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DOI：
10.1111/vco.12778
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发表时间：
2021-11-03
影响因子：
2.1
通讯作者：
Warita, Katsuhiko
中科院分区：
文献类型：
--
作者：
Ishikawa, Takuro;Osaki, Tomohiro;Warita, Katsuhiko
上皮间质转化（EMT）是癌症进展的基础，有助于恶性特性的获得。他汀类降胆固醇药物在体外和体内表现出多效抗癌作用，许多流行病学研究报告了他汀类药物的使用与降低癌症死亡率之间的相关性。我们之前已经表明，人类癌细胞对他汀类药物抗增殖作用的敏感性有所不同，并且他汀类药物对人类癌症中的间充质样细胞比上皮样细胞更有效。在兽医学中关于他汀类药物应用于癌症治疗的报道很少，并且尚未研究犬癌细胞对他汀类药物敏感性的差异。在这项研究中，我们旨在阐明 11 种源自乳腺、鳞状细胞癌、肺癌和黑色素瘤的犬癌细胞系对阿托伐他汀的敏感性与上皮/间质状态之间的相关性。犬癌细胞对阿托伐他汀的敏感性不同，48小时时IC50值范围为5.92至71.5μM，高于临床上用他汀类药物治疗达到的血浆浓度。阿托伐他汀优先减弱间充质样细胞的增殖。特别是，对他汀类药物高度敏感的细胞的特征是 EMT 诱导转录因子 ZEB 家族的异常表达。然而，高度敏感细胞中的ZEB2沉默不会诱导对阿托伐他汀的耐药性。综上所述，这些结果表明ZEB的高表达是对他汀类药物高度敏感的细胞的一个特征，并且可以作为预测癌症是否对他汀类药物敏感的分子标记，尽管ZEB本身并不赋予他汀类药物敏感性。
The epithelial-to-mesenchymal transition (EMT) is fundamental in cancer progression and contributes to the acquisition of malignant properties. The statin class of cholesterol-lowering drugs exhibits pleiotropic anticancer effects in vitro and in vivo, and many epidemiologic studies have reported a correlation between statin use and reduced cancer mortality. We have shown previously that sensitivity to the anti-proliferative effect of statins varies among human cancer cells and statins are more effective against mesenchymal-like cells than epithelial-like ones in human cancers. There have only been few reports on the application of statins to cancer therapy in veterinary medicine, and differences in statin sensitivity among canine cancer cells have not been examined. In this study, we aimed to clarify the correlation between sensitivity to atorvastatin and epithelial/mesenchymal states in 11 canine cancer cell lines derived from mammary gland, squamous cell carcinoma, lung, and melanoma. Sensitivity to atorvastatin varied among canine cancer cells, with IC50 values ranging from 5.92 to 71.5 mu M at 48 h, which were higher than the plasma concentrations clinically achieved with statin therapy. Atorvastatin preferentially attenuated the proliferation of mesenchymal-like cells. In particular, highly statin-sensitive cells were characterized by aberrant expression of the ZEB family of EMT-inducing transcription factors. However, ZEB2 silencing in highly sensitive cells did not induce resistance to atorvastatin. Taken together, these results suggest that high expression of ZEB is a characteristic of highly statin-sensitive cells and could be a molecular marker for predicting whether cancers are sensitive to statins, though ZEB itself does not confer statin sensitivity.