Involvement of the Mitochondrial Pathway in p53-Independent Apoptosis Induced by p28GANK Knockdown in Hep3B Cells
Involvement of the Mitochondrial Pathway in p53-Independent Apoptosis Induced by p28GANK Knockdown in Hep3B Cells
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DOI：
10.1159/000227831
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发表时间：
2009-08
影响因子：
1.7
通讯作者：
Juan Wang;X. Wang;L. Zhang;S. Xie;Z. L. Li;Y. J. Li;H. H. Li-H.;F. Jiao
中科院分区：
文献类型：
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作者：
Juan Wang;X. Wang;L. Zhang;S. Xie;Z. L. Li;Y. J. Li;H. H. Li-H.;F. Jiao
众所周知，TP53可能介导了抗癌药物引发的细胞凋亡。然而，越来越多的证据表明，在大约50%的人类癌症中，TP53可能因突变和/或缺失而失活，因此可能导致对治疗药物的显著耐药。因此，开发新的方法来提高携带突变TP53的癌细胞中治疗剂的效率可能会对癌症的治疗产生重大影响。P28GANK(PSMD10基因的别名)是一种在肝细胞癌中过度表达的新癌基因，已有报道通过RNA干扰(RNAi)敲除p28GANK可以诱导TP53缺失的肝癌细胞株HepG2的凋亡。由于在肝细胞癌中存在高频率的TP53突变，因此了解p28GANK基因敲除诱导的细胞凋亡是否也在TP53阴性的肝细胞癌细胞中起作用是相关的。在这里，我们研究了Adsi28GANK诱导TP53阴性的肝癌细胞株Hep3B的凋亡。我们的结果表明，p28GANK-基因敲除诱导了活性氧物种(ROS)的产生，而ROS又激活了p38。由于p38可以向bax发出信号，p38的激活可能导致线粒体跨膜电位(Δψm)的丧失，细胞色素c从线粒体释放到胞浆，并激活caspase9，最终触发线粒体的凋亡途径。
It is well known that TP53 may mediate apoptosis triggered by anticancer drugs. However, accumulating evidence indicates that TP53 may be inactivated by mutations and/or deletions in about 50% of human cancers and, as such, may lead to pronounced resistance to therapeutic agents. Thus, the development of new approaches to improve the efficiency of therapeutic agents in cancer cells harboring mutant TP53 may have a significant impact on cancer treatment. It has been reported that knockdown by RNA interference (RNAi) of p28GANK (an alias of the gene PSMD10), a novel oncogene over-expressed in hepatocellular carcinoma (HCC), can induce apoptosis in HepG2, a TP53-intact HCC cell line. Because of the high frequency TP53 mutations in HCC, it is relevant to know whether p28GANK knockdown-induced apoptosis is also operational in TP53-negative HCC cells. Here, we investigated Adsip28GANK-induced apoptosis in the TP53-negative HCC cell line Hep3B. Our results indicate that p28GANK-knockdown induces the generation of reactive oxygen species (ROS), which in turn activates p38. Since p38 can signal to Bax, its activation may lead to mitochondrial transmembrane potential (Δψm) loss, cytochrome c release from mitochondria to cytosol, and caspase-9 activation, eventually triggering the mitochondrial pathway of apoptosis.