Sensitization to the lysosomal cell death pathway by oncogene-induced down-regulation of lysosome-associated membrane proteins 1 and 2
Sensitization to the lysosomal cell death pathway by oncogene-induced down-regulation of lysosome-associated membrane proteins 1 and 2
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DOI：
10.1158/0008-5472.can-08-0463
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发表时间：
2008-08-15
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：
Fehrenbacher, Nicole;Bastholm, Lone;Jaattela, Marja
溶酶体半胱氨酸组织蛋白酶的表达和活性与肿瘤的转移能力和侵袭性有关。在这里，我们发现用v-H-ras或c-src（Y527F）转化小鼠胚胎成纤维细胞改变了溶酶体的分布、密度和超微结构，以细胞外信号调节激酶（ERK）和组织蛋白酶依赖的方式降低了溶酶体相关膜蛋白（LAMP-1和LAMP-2）的水平，并使细胞对各种抗肿瘤药物（如顺铂、依托泊苷、阿霉素和西拉米辛）诱导的溶酶体细胞死亡通路敏感。重要的是，K-ras和erbb2分别在人类结肠癌和乳腺癌细胞中引发类似的erk介导的半胱氨酸组织蛋白酶激活、组织蛋白酶依赖的lamp下调和药物敏感性增加。值得注意的是，通过异位表达或组织蛋白酶抑制剂重建LAMP水平可以保护转化的细胞免受溶酶体细胞死亡途径的影响。此外，敲低lamp1或lamp2足以使细胞敏感于siramesine诱导的细胞死亡和光氧化诱导的溶酶体不稳定。因此，转化相关的erk介导的半胱氨酸组织蛋白酶表达和活性的上调导致lamp水平的降低，这反过来又有助于转化细胞对触发溶酶体膜渗透的药物的敏感性增强。这些数据表明，具有高半胱氨酸组织蛋白酶水平的侵袭性癌症对溶酶体细胞死亡途径特别敏感，并鼓励进一步开发溶酶体靶向化合物用于癌症治疗。
Expression and activity of lysosomal cysteine cathepsins correlate with the metastatic capacity and aggressiveness of tumors. Here, we show that transformation of murine embryonic fibroblasts with v-H-ras or c-src(Y527F) changes the distribution, density, and ultrastructure of the lysosomes, decreases the levels of lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in an extracellular signal-regulated kinase (ERK)- and cathepsin-dependent manner, and sensitizes the cells to lysosomal cell death pathways induced by various anticancer drugs (i.e., cisplatin, etoposide, doxorubicin, and siramesine). Importantly, K-ras and erbb2 elicit a similar ERK-mediated activation of cysteine cathepsins, cathepsin-dependent down-regulation of LAMPs, and increased drug sensitivity in human colon and breast carcinoma cells, respectively. Notably, reconstitution of LAMP levels by ectopic expression or by cathepsin inhibitors protects transformed cells against the lysosomal cell death pathway. Furthermore, knockdown of either lamp1 or lamp2 is sufficient to sensitize the cells to siramesine-induced cell death and photo-oxidation-induced lysosomal destabilization. Thus, the trans formation-associated ERK-mediated up-regulation of cysteine cathepsin expression and activity leads to a decrease in the levels of LAMPs, which in turn contributes to the enhanced sensitivity of transformed cells to drugs that trigger lysosomal membrane permeabilization. These data indicate that aggressive cancers with high cysteine cathepsin levels are especially sensitive to lysosomal cell death pathways and encourage the further development of lysosome-targeting compounds for cancer therapy.