Sensitization to the lysosomal cell death pathway upon immortalization and transformation
Sensitization to the lysosomal cell death pathway upon immortalization and transformation
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DOI：
10.1158/0008-5472.can-04-1427
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发表时间：
2004-08-01
期刊：
影响因子：
11.2
通讯作者：
Jäättelä, M
中科院分区：
文献类型：
--
作者：
Fehrenbacher, N;Gyrd-Hansen, M;Jäättelä, M
肿瘤发生与改变细胞对程序性细胞死亡的易感性的几种变化有关。在这里，我们表明，永生化和转化敏感的细胞，特别是半胱氨酸组织蛋白酶介导的溶酶体死亡途径。自发永生化使野生型海洋胚胎成纤维细胞（MEFs）对肿瘤坏死因子（TNF）介导的细胞毒性的敏感性增加>1000倍，而溶酶体半胱氨酸蛋白酶组织蛋白酶B（CathB）缺陷的永生化MEFs保留了原代细胞的抗性表型。这种效应对于半胱氨酸组织蛋白酶是特异性的，因为也缺乏组织蛋白酶L（一种溶酶体半胱氨酸蛋白酶），但不缺乏组织蛋白酶D（一种溶酶体半胱氨酸蛋白酶）或半胱天冬酶-3（经典细胞凋亡中的主要执行者蛋白酶）抑制MEFs对TNF的永生化相关致敏作用。癌基因驱动的永生化MEFs的转化与组织蛋白酶表达的急剧增加和对半胱氨酸组织蛋白酶介导的死亡途径的额外敏化相关。重要的是，CathB的外源性表达部分逆转了永生化CathB缺陷MEFs的耐药表型，并且通过药理学抑制剂或RNA干扰抑制CathB活性减弱了TNF诱导的永生化和转化野生型细胞的细胞毒性。因此，肿瘤发生相关的变化，在溶酶体可能会抵消癌症的进展，并提高敏感细胞程序性细胞死亡的治疗反应。
Tumorigenesis is associated with several changes that alter the cellular susceptibility to programmed cell death. Here, we show that immortalization and transformation sensitize cells in particular to the cysteine cathepsin-mediated lysosomal death pathway. Spontaneous immortalization increased the susceptibility of wild-type marine embryonic fibroblasts (MEFs) to tumor necrosis factor (TNF)-mediated cytotoxicity >1000-fold, whereas immortalized MEFs deficient for lysosomal cysteine protease cathepsin B (CathB) retained the resistant phenotype of primary cells. This effect was specific for cysteine cathepsins, because also lack of cathepsin L (a lysosomal cysteine protease), but not that of cathepsin D (a lysosomal aspartyl protease) or caspase-3 (the major executioner protease in classic apoptosis) inhibited the immortalization-associated sensitization of MEFs to TNF. Oncogene-driven transformation of immortalized MEFs was associated with a dramatic increase in cathepsin expression and additional sensitization to the cysteine cathepsin-mediated death pathway. Importantly, exogenous expression of CathB partially reversed the resistant phenotype of immortalized CathB-deficient MEFs, and the inhibition of CathB activity by pharmacological inhibitors or RNA interference attenuated TNF-induced cytotoxicity in immortalized and transformed wild-type cells. Thus, tumorigenesis-associated changes in lysosomes may counteract cancer progression and enhance therapeutic responses by sensitizing cells to programmed cell death.