Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7
Inhibition of cathepsin L lowers the apoptotic threshold of glioblastoma cells by up-regulating p53 and transcription of caspases 3 and 7
复制标题
DOI：
10.1007/s10495-011-0600-6
复制
发表时间：
2011-07-01
期刊：
影响因子：
7.2
通讯作者：
Lah, Tamara
中科院分区：
文献类型：
--
作者：
Kenig, Sasa;Frangez, Robert;Lah, Tamara
尽管在癌症治疗方面取得了所有进展，但胶质母细胞瘤，中枢神经系统最恶性的肿瘤，仍然是一种晚期疾病，迫切需要新的治疗方法。化疗与降低癌细胞凋亡阈值的修饰相结合可能是有效的。组织蛋白酶L抑制被认为是这种修饰之一，但组织蛋白酶L抗凋亡活性的机制在很大程度上是未知的。在本研究中，我们表明，在U87胶质母细胞瘤细胞，组织蛋白酶L存在于细胞核中，并调节效应半胱天冬酶3和7的转录。在组织蛋白酶L低表达的细胞中，调节caspase 7表达的转录因子p53和p53在细胞核中积累。p53在这一过程中的重要性是突出的事实，即在U87细胞与抑制p53转录活性或在p53阴性细胞U251，组织蛋白酶L抑制不影响半胱天冬酶7的表达和细胞凋亡的水平有最小的影响。由于胶质母细胞瘤中p53途径经常发生突变，因此在使用组织蛋白酶L抑制剂进行胶质母细胞瘤治疗之前需要考虑我们研究的结果，并表明这种辅助治疗可能仅对p53野生型胶质母细胞瘤患者的一个亚群有效。
Despite all the progress in cancer treatment, glioblastoma, the most malignant tumor of the central nervous system, remains a terminal disease and new therapeutic approaches are urgently needed. A combination of chemotherapy with modifications that lower the apoptotic threshold of cancer cells could be effective. Cathepsin L inhibition was suggested as one of such modifications but the mechanism of cathepsin L anti-apoptotic activity is largely unknown. In the present study we show that, in U87 glioblastoma cells, cathepsin L is present in the nucleus and regulates the transcription of effector caspases 3 and 7. In cells with low cathepsin L expression, p53 and prohibitin-transcription factors that regulate caspase 7 expression-accumulate in the nuclei. The importance of p53 in this process is highlighted by the fact that in U87 cells with inhibited p53 transcriptional activity or in p53-negative cells U251, cathepsin L inhibition did not influence caspase 7 expression and had minimal effect on the level of apoptosis. Since p53 pathways are often mutated in glioblastoma, the findings of our study need to be considered before using cathepsin L inhibition for glioblastoma therapy and suggest that such adjuvant therapy may be effective only for a subpopulation of p53 wild type glioblastoma patients.