Lens epithelium-derived growth factor is an Hsp70-2 regulated guardian of lysosomal stability in human cancer
Lens epithelium-derived growth factor is an Hsp70-2 regulated guardian of lysosomal stability in human cancer
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DOI：
10.1158/0008-5472.can-06-4121
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发表时间：
2007-03-15
期刊：
影响因子：
11.2
通讯作者：
Jaattela, Marja
中科院分区：
文献类型：
--
作者：
Daugaard, Mads;Kirkegaard-Sorensen, Thomas;Jaattela, Marja
热休克蛋白70 - 2（Hsp70 - 2）是精母细胞和癌细胞生长所必需的分子伴侣蛋白。在这里，我们表明，热休克蛋白70 - 2消耗触发溶酶体膜透化和组织蛋白酶依赖性细胞死亡，并确定透镜上皮衍生生长因子（LEDGF）作为一个热休克蛋白70 - 2调节的监护人的溶酶体稳定性在人类癌症。在癌细胞中LEDGF的敲低诱导溶酶体膜的不稳定，随后是半胱天冬酶非依赖性和Bcl-2抗性细胞死亡。因此，异位LEDGF稳定溶酶体并保护癌细胞免受由触发溶酶体细胞死亡途径的抗癌剂诱导的细胞毒性。值得注意的是，异位LEDGF也增加了免疫缺陷小鼠中人癌细胞的致瘤潜力，并且LEDGF表达在人乳腺癌和膀胱癌中增加，与浸润性膀胱癌中的Hsp70 - 2表达相关。综上所述，这些数据揭示LEDGF作为控制半胱天冬酶非依赖性溶酶体细胞死亡途径的致癌蛋白。
Heat shock protein 70-2 (Hsp70-2) is a chaperone protein essential for the growth of spermatocytes and cancer cells. Here, we show that Hsp70-2 depletion triggers lysosomal membrane permeabilization and cathepsin-dependent cell death and identify lens epithelium-derived growth factor (LEDGF) as an Hsp70-2-regulated guardian of lysosomal stability in human cancer. Knockdown of LEDGF in cancer cells induces destabilization of lysosomal membranes followed by caspase-independent and Bcl-2-resistant cell death. Accordingly, ectopic LEDGF stabilizes lysosomes and protects cancer cells against cytotoxicity induced by anticancer agents that trigger the lysosomal cell death pathway. Remarkably, ectopic LEDGF also increases the tumorigenic potential of human cancer cells in immunodeficient mice, and LEDGF expression is increased in human breast and bladder carcinomas correlating with that of Hsp70-2 in invasive bladder cancer. Taken together, these data reveal LEDGF as an oncogenic protein that controls a caspase-independent lysosomal cell death pathway.