Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-xL ratio
Wip1 sensitizes p53-negative tumors to apoptosis by regulating the Bax/Bcl-xL ratio
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DOI：
10.4161/cc.19901
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发表时间：
2012-05-15
期刊：
影响因子：
4.3
通讯作者：
Demidov, Oleg N.
中科院分区：
文献类型：
--
作者：
Goloudina, Anastasia R.;Mazur, Sharlyn J.;Demidov, Oleg N.
Wip 1是一种应激反应磷酸酶，可负调节包括p53在内的几种肿瘤抑制因子。在相当一部分肿瘤中，Wip 1的过度表达或扩增会损害p53功能;抑制Wip 1活性是改善这些肿瘤治疗的有吸引力的策略。然而，超过一半的人类肿瘤在p53基因中含有突变或失去了两个等位基因。最近，我们观察到在缺乏野生型p53的癌细胞中，Wip 1表达的减少是无效的，而令人惊讶的是，Wip 1的过表达增加了抗癌药物的敏感性。增加的敏感性是由于通过增加促凋亡蛋白Bax的水平和降低抗凋亡蛋白Bcl-x（L）的水平而激活凋亡的内在途径。我们发现Wip 1和转录因子RUNX 2的相互作用，特别是通过RUNX 2磷酸化S432的去磷酸化，导致Bax的表达增加。有趣的是，Wip 1的过度表达仅在p53阴性肿瘤细胞中增加药物敏感性，同时保护野生型含p53的正常细胞免受药物诱导的侧支损伤。在此，我们提供了Wip 1过表达通过负调节NF κ B活性降低Bcl-x（L）表达的证据。因此，Wip 1过表达通过分别影响Bax和Bcl-x（L）蛋白水平而增加p53阴性癌细胞对抗癌药物的敏感性。
Wip1 is a stress-response phosphatase that negatively regulates several tumor suppressors, including p53. In a sizeable fraction of tumors, overexpression or amplification of Wip1 compromises p53 functions; inhibition of Wip1 activity is an attractive strategy for improving treatment of these tumors. However, over half of human tumors contain mutations in the p53 gene or have lost both alleles. Recently, we observed that in cancer cells lacking wild-type p53, reduction of Wip1 expression was ineffective, whereas, surprisingly, overexpression of Wip1 increased anticancer drug sensitivity. The increased sensitivity resulted from activation of the intrinsic pathway of apoptosis through increased levels of the pro-apoptotic protein Bax and decreased levels of the anti-apoptotic protein Bcl-x(L). We showed that interaction of Wip1 and the transcription factor RUNX2, specifically through dephosphorylation of RUNX2 phospho-S432, resulted in increased expression of Bax. Interestingly, overexpression of Wip1 increased drug sensitivity only in the p53-negative tumor cells while protecting the wild-type, p53-containing normal cells from drug-induced collateral injury. Here, we provide evidence that Wip1 overexpression decreases expression of Bcl-x(L) through negative regulation of NF kappa B activity. Thus, Wip1 overexpression increases the sensitivity of p53-negative cancer cells to anticancer drugs by separately affecting Bax and Bcl-x(L) protein levels.