来自美国爱因斯坦医学院的一组研究人员通过体内和体外实验证实,分子伴侣介导的自噬作用在肿瘤发生中起着重要的作用,近日将其研究结果发表在《科学》(Science)杂志上。
细胞的自噬作用在维持细胞内环境的稳定中起重要作用,自噬作用的2条基本通路是巨噬作用和分子伴侣介导的自噬作用(CMA)。巨噬作用在肿瘤中的作用已经阐明,抑制巨噬作用可诱发肿瘤的发生。
由于正常细胞通过上调CMA通路来对抗巨噬作用的抑制,研究者将不同肿瘤细胞中的CMA水平调至均一水平,而不考虑巨噬作用的水平。他们还证实了在不同的人类肿瘤细胞中CMA的水平均有不同程度的上调。
在体外试验中,研究者发现CMA通过维持肿瘤细胞的代谢特征参与肿瘤细胞的增殖。随后他们将人类肺癌移植到小鼠身上进行实验,发现在体内的肿瘤细胞也依赖于CMA。抑制CMA后,小鼠移植癌的生长会延迟,且转移的数目也减少,甚至出现肿瘤消退的现象。后来他们又使用2种不同的黑素瘤细胞系进行实验,也得到了同样的结果。
该研究结果表明,靶向该自噬作用通路或许可为抑制肿瘤的发生提供思路。(生物谷 Bioon.com)
doi:10.1126/scitranslmed.3003182PMC:
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Chaperone-Mediated Autophagy Is Required for Tumor Growth
Maria Kon, Roberta Kiffin, Hiroshi Koga, Javier Chapochnick, Fernando Macian, Lyuba Varticovski and Ana Maria Cuervo
The cellular process of autophagy (literally “self-eating”) is important for maintaining the homeostasis and bioenergetics of mammalian cells. Two of the best-studied mechanisms of autophagy are macroautophagy and chaperone-mediated autophagy (CMA). Changes in macroautophagy activity have been described in cancer cells and in solid tumors, and inhibition of macroautophagy promotes tumorigenesis. Because normal cells respond to inhibition of macroautophagy by up-regulation of the CMA pathway, we aimed to characterize the CMA status in different cancer cells and to determine the contribution of changes in CMA to tumorigenesis. Here, we show consistent up-regulation of CMA in different types of cancer cells regardless of the status of macroautophagy. We also demonstrate an increase in CMA components in human cancers of different types and origins. CMA is required for cancer cell proliferation in vitro because it contributes to the maintenance of the metabolic alterations characteristic of malignant cells. Using human lung cancer xenografts in mice, we confirmed the CMA dependence of cancer cells in vivo. Inhibition of CMA delays xenograft tumor growth, reduces the number of cancer metastases, and induces regression of existing human lung cancer xenografts in mice. The fact that similar manipulations of CMA also reduce tumor growth of two different melanoma cell lines suggests that targeting this autophagic pathway may have broad antitumorigenic potential.