Itraconazole suppresses the growth of glioblastoma through induction of autophagy Involvement of abnormal cholesterol trafficking
Itraconazole suppresses the growth of glioblastoma through induction of autophagy Involvement of abnormal cholesterol trafficking
复制标题
伊曲康唑通过诱导自噬抑制胶质母细胞瘤的生长参与异常胆固醇运输
DOI：
10.4161/auto.28912
复制
发表时间：
2014-07-01
期刊：
影响因子：
13.3
通讯作者：
Wei, Yuquan
中科院分区：
文献类型：
--
作者：
Liu, Rui;Li, Jingyi;Wei, Yuquan
胶质母细胞瘤是最具侵袭性且预后不良的人类癌症之一，因此迫切需要新的治疗策略来管理胶质母细胞瘤患者。伊曲康唑是一种传统的抗真菌药物，由于其抑制细胞增殖和肿瘤血管生成的作用而被认为是一种潜在的新型抗癌药物；然而，所涉及的分子机制尚不清楚。在这里，我们表明伊曲康唑抑制胶质母细胞瘤细胞在体外和体内的增殖。值得注意的是，我们证明了伊曲康唑治疗可诱导胶质母细胞瘤细胞自噬进展，而自噬阻断可显著逆转伊曲康唑的抗增殖活性，这表明自噬对伊曲康唑治疗有抗肿瘤作用。功能研究发现，伊曲康唑通过降低SCP2水平，延缓胆固醇从晚期核内体和溶酶体向质膜的运输，从而抑制AKT1-MTOR信号，诱导自噬，最终抑制细胞增殖。本研究为伊曲康唑抗肿瘤作用的分子机制提供了新的认识，为伊曲康唑的药理研究和临床合理应用提供了依据。
Glioblastoma is one of the most aggressive human cancers with poor prognosis, and therefore a critical need exists for novel therapeutic strategies for management of glioblastoma patients. Itraconazole, a traditional antifungal drug, has been identified as a novel potential anticancer agent due to its inhibitory effects on cell proliferation and tumor angiogenesis; however, the molecular mechanisms involved are still unclear. Here, we show that itraconazole inhibits the proliferation of glioblastoma cells both in vitro and in vivo. Notably, we demonstrate that treatment with itraconazole induces autophagic progression in glioblastoma cells, while blockage of autophagy markedly reverses the antiproliferative activities of itraconazole, suggesting an antitumor effect of autophagy in response to itraconazole treatment. Functional studies revealed that itraconazole retarded the trafficking of cholesterol from late endosomes and lysosomes to the plasma membrane by reducing the levels of SCP2, resulting in repression of AKT1-MTOR signaling, induction of autophagy, and finally inhibition of cell proliferation. Together, our studies provide new insights into the molecular mechanisms regarding the antitumor activities of itraconazole, and may further assist both the pharmacological investigation and rational use of itraconazole in potential clinical applications.