Autophagy triggered by magnolol derivative negatively regulates angiogenesis.
Autophagy triggered by magnolol derivative negatively regulates angiogenesis.
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DOI：
10.1038/cddis.2013.399
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发表时间：
2013-10-31
影响因子：
9
通讯作者：
Malik F
中科院分区：
文献类型：
--
作者：
Kumar S;Guru SK;Pathania AS;Kumar A;Bhushan S;Malik F
血管生成在肿瘤的进展和转移中具有关键作用，靶向内皮细胞增殖已成为预防癌症的有希望的治疗策略。先前的研究已经揭示了血管生成和自噬的过程与其对肿瘤发生的结果之间的复杂关联。自噬，也被称为II型细胞死亡，已被确定为耐药癌细胞中细胞杀伤的另一种方式。然而，其参与化学抗性和肿瘤促进也是众所周知的。本研究利用天然产物厚朴酚的衍生物Ery 5，在体外和体内模型系统中研究了自噬与血管生成之间的关系。我们发现Ery 5在人脐静脉内皮细胞和PC-3细胞中引发的强大的自噬，抑制血管生成并引起细胞死亡，而不依赖于细胞凋亡。Ery 5诱导的自噬能有效抑制细胞增殖、迁移、侵袭和管腔形成。我们进一步证明，当自噬通过3-甲基腺嘌呤和敲低关键自噬蛋白ATG 7和微管相关蛋白轻链3被抑制时，Ery 5介导的自噬和随后的血管生成抑制被逆转。在评估自噬对血管生成的负调节时，有趣的是发现由VEGF和CoCl 2处理产生的血管生成环境显著下调Ery 5诱导的自噬和自噬性细胞死亡。这些研究在揭示自噬在血管生成调节中的重要作用的同时，也表明自噬的有效调节剂可以导致在抗肿瘤性癌症中开发有效的治疗剂。
Angiogenesis has a key role in the tumor progression and metastasis; targeting endothelial cell proliferation has emerged as a promising therapeutic strategy for the prevention of cancer. Previous studies have revealed a complex association between the process of angiogenesis and autophagy and its outcome on tumorigenesis. Autophagy, also known as type-II cell death, has been identified as an alternative way of cell killing in apoptotic-resistant cancer cells. However, its involvement in chemoresistance and tumor promotion is also well known. In this study, we used a derivate of natural product magnolol (Ery5), a potent autophagy inducer, to study the association between the autophagy and angiogenesis in both in vitro and in vivo model system. We found that the robust autophagy triggered by Ery5, inhibited angiogenesis and caused cell death independent of the apoptosis in human umbilical cord vein endothelial cells and PC-3 cells. Ery5 induced autophagy effectively inhibited cell proliferation, migration, invasion and tube formation. We further demonstrated that Ery5-mediated autophagy and subsequent inhibition of angiogenesis was reversed when autophagy was inhibited through 3-methyl adenine and knocking down of key autophagy proteins ATG7 and microtubule-associated protein light chain 3. While evaluating the negative regulation of autophagy on angiogenesis, it was interesting to find that angiogenic environment produced by the treatment of VEGF and CoCl2 remarkably downregulated the autophagy and autophagic cell death induced by Ery5. These studies, while disclosing the vital role of autophagy in the regulation of angiogenesis, also suggest that the potent modulators of autophagy can lead to the development of effective therapeutics in apoptosis-resistant cancer.
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影响因子：
11.2
作者：
Hu YL;DeLay M;Jahangiri A;Molinaro AM;Rose SD;Carbonell WS;Aghi MK
通讯作者：
Aghi MK
影响因子：
5.1
作者：
Kumar, Ajay;Malik, Fayaz;Singh, Jaswant
通讯作者：
Singh, Jaswant
影响因子：
6.7
作者：
Jada, Srinivas;Doma, Mahendhar Reddy;Kumar, H. M. Sampath
通讯作者：
Kumar, H. M. Sampath
影响因子：
5.5
作者：
Du, Jianhai;Teng, Ru-Jeng;Shi, Yang
通讯作者：
Shi, Yang
影响因子：
9.7
作者：
Kondo, T;Ohta, T;Kaji, K
通讯作者：
Kaji, K