Proteasome Inhibitors Induce p53-Independent Apoptosis in Human Cancer Cells
Proteasome Inhibitors Induce p53-Independent Apoptosis in Human Cancer Cells
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DOI：
10.1016/j.ajpath.2010.11.010
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发表时间：
2011-01-01
影响因子：
6
通讯作者：
Gartel, Andrei L.
中科院分区：
文献类型：
--
作者：
Pandit, Bulbul;Gartel, Andrei L.
蛋白酶体抑制剂用于治疗人类癌症，但其作用机制尚不完全清楚。例如，抑癌基因P53的作用就存在争议。我们通过使用具有不同P53状态的同基因人类癌细胞株，重新评估了P53在蛋白酶体抑制剂诱导的细胞凋亡中的作用。我们发现，众所周知的蛋白酶体抑制剂，如MG132和Bortezomib，以及最近发现的蛋白酶体抑制剂硫代链球菌，可以诱导人类癌细胞系非依赖于P53的凋亡，这与非依赖于P53的诱导促凋亡的Noxa相关，而与Puma蛋白无关。此外，这些药物抑制了几种癌细胞的生长，而不依赖于P53基因的状态。值得注意的是，与野生型p53基因敲除的亲本细胞相比，硫链菌素诱导p53基因敲除的HepG2细胞更有效地诱导了凋亡。我们的数据证实，蛋白酶体抑制剂通常诱导人类癌细胞中不依赖于P53的凋亡。(Am J Pathol2011,178：355-360；doi：10.1016/j.ajpath.2010.11.010)
Proteasome inhibitors are used against human cancer, but their mechanisms of action are not entirely understood. For example, the role of the tumor suppressor p53 is controversial. We reevaluated the role of p53 in proteasome inhibitor-induced apoptosis by using isogenic human cancer cell lines with different p53 status. We found that well-known proteasome inhibitors such as MG132 and bortezomib, as well as the recently discovered proteasome inhibitor thiostrepton, induced p53-independent apoptosis in human cancer cell lines that correlated with p53-independent induction of proapoptotic Noxa but not Puma protein. In addition, these drugs inhibited growth of several cancer cell lines independently of p53 status. Notably, thiostrepton induced more potent apoptosis in HepG2 cells with p53 knockdown than in parental cells with wild-type p53. Our data confirm that proteasome inhibitors generally induce p53-independent apoptosis in human cancer cells. (Am J Pathol 2011, 178:355-360; DOI: 10.1016/j.ajpath.2010.11.010)