Zhang Huang-Ge, Kim Helen, Liu Cunren, Yu Shaohua, Wang Jianhua, Grizzle William E, Kimberly Robert P, Barnes Stephen
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Biochim Biophys Acta. 2007 Jul;1773(7):1116-23. doi: 10.1016/j.bbamcr.2007.04.015. Epub 2007 May 1.
An important characteristic of tumors is that they at some point in their development overcome the surveillance of the immune system. Tumors secrete exosomes, multivesicular bodies containing a distinct set of proteins that can fuse with cells of the circulating immune system. Purified exosomes from TS/A breast cancer cells, but not non-exosomal fractions, inhibit (at concentrations of nanograms per ml protein) IL-2-induced natural killer (NK) cell cytotoxicity. The dietary polyphenol, curcumin (diferuloylmethane), partially reverses tumor exosome-mediated inhibition of natural killer cell activation, which is mediated through the impairment of the ubiquitin-proteasome system. Exposure of mouse breast tumor cells to curcumin causes a dose-dependent increase in ubiquitinated exosomal proteins compared to those in untreated TS/A breast tumor cells. Furthermore, exosomes isolated from tumor cells pretreated with curcumin have a much attenuated inhibition of IL-2 stimulated NK cell activation. Jak3-mediated activation of Stat5 is required for tumor cytotoxicity of IL-2 stimulated NK cells. TS/A tumor exosomes strongly inhibit activation of Stat5, whereas the tumor exosomes isolated from curcumin-pretreated tumor cells have a lowered potency for inhibition of IL-2 stimulated NK cell cytotoxicity. These data suggest that partial reversal of tumor exosome-mediated inhibition of NK cell tumor cytotoxicity may account for the anti-cancer properties of curcumin.
肿瘤的一个重要特征是它们在发展的某个阶段会克服免疫系统的监视。肿瘤会分泌外泌体,即含有一组独特蛋白质的多囊泡体,这些外泌体能够与循环免疫系统的细胞融合。来自TS/A乳腺癌细胞的纯化外泌体,而非非外泌体部分,(在每毫升蛋白质纳克浓度下)能抑制白细胞介素-2诱导的自然杀伤(NK)细胞的细胞毒性。膳食多酚姜黄素(二阿魏酰甲烷)能部分逆转肿瘤外泌体介导的对自然杀伤细胞激活的抑制作用,这种抑制作用是通过泛素-蛋白酶体系统的损伤介导的。与未处理的TS/A乳腺癌细胞相比,将小鼠乳腺肿瘤细胞暴露于姜黄素会导致泛素化外泌体蛋白呈剂量依赖性增加。此外,从用姜黄素预处理的肿瘤细胞中分离出的外泌体对白细胞介素-2刺激的NK细胞激活的抑制作用大大减弱。白细胞介素-2刺激的NK细胞的肿瘤细胞毒性需要Jak3介导的Stat5激活。TS/A肿瘤外泌体强烈抑制Stat5的激活,而从姜黄素预处理的肿瘤细胞中分离出的肿瘤外泌体抑制白细胞介素-2刺激的NK细胞细胞毒性的能力降低。这些数据表明,肿瘤外泌体介导的对NK细胞肿瘤细胞毒性的抑制作用的部分逆转可能是姜黄素抗癌特性的原因。