HtrA1 sensitizes ovarian cancer cells to cisplatin-induced cytotoxicity by targeting XIAP for degradation.
HtrA1 sensitizes ovarian cancer cells to cisplatin-induced cytotoxicity by targeting XIAP for degradation.
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DOI：
10.1002/ijc.26044
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发表时间：
2012-03-01
影响因子：
6.4
通讯作者：
Shridhar, Viji
中科院分区：
文献类型：
--
作者：
He, Xiaoping;Khurana, Ashwani;Maguire, Jacie L.;Chien, Jeremy;Shridhar, Viji
HTRA1是丝氨酸蛋白酶家族的成员之一，已被发现与卵巢癌的化疗耐药有关，但其潜在机制尚不清楚。利用基于混合物的多肽库方法，我们先前发现X-连锁的凋亡抑制蛋白(XIAP)是HtrA1的潜在底物，它是凋亡抑制蛋白(IAPs)家族的成员。这项工作的目的是研究HtrA1和XIAP蛋白之间的联系及其与卵巢癌化疗耐药的关系。结果表明，重组XIAP在体外可被纯化的野生型HtrA1降解，但不能被突变体HtrA1降解。免疫共沉淀实验表明，HtrA1与XIAP在体内形成了蛋白质复合体，与体外实验结果一致。HtrA1异位表达导致OV167和OV202卵巢癌细胞XIAP水平降低，而HtrA1基因敲除导致SKOV3卵巢癌细胞XIAP水平升高。此外，HtrA1在OV202细胞中的过表达提高了细胞对顺铂诱导的细胞凋亡的敏感性，这一作用可被XIAP表达的增加所逆转。顺铂可增强HtrA1诱导的XIAP的切割。综上所述，我们的实验确定XIAP是HtrA1的一种新的底物，HtrA1对XIAP的降解有助于细胞对化疗的反应，提示恢复HtrA1的表达可能是一种有前景的卵巢癌治疗策略。
HtrA1, a member of serine protease family, has been previously found to be involved in resistance to chemotherapy in ovarian cancer although the underlying mechanism is not clear. Using mixture-based oriented peptide library approach, we previously identified X-linked inhibitor of apoptosis protein (XIAP), a member of the inhibitor of apoptosis proteins (IAPs) family as a potential substrate of HtrA1. The aim of this work is to investigate the link between HtrA1 and XIAP proteins and their relationships with chemoresistance in ovarian cancer. Our results showed that recombinant XIAP was degraded by purified wild type HtrA1 but not mutant HtrA1 in vitro. Consistent with the in vitro data, co-immunoprecipitation assays showed that HtrA1 and XIAP formed a protein complex in vivo. Ectopic expression of HtrA1 led to decreased level of XIAP in OV167 and OV202 ovarian cancer cells, while knockdown of HtrA1 resulted in increased level of XIAP in SKOV3 ovarian cancer cells. Furthermore, over-expression of HtrA1 in OV202 cells promoted cell sensitivity to cisplatin-induced apoptosis which could be reversed by increased expression of XIAP. The cleavage of XIAP induced by HtrA1 was enhanced by cisplatin treatment. Taken together, our experiments have identified XIAP as a novel substrate of HtrA1 and the degradation of XIAP by HtrA1 contributes to cell response to chemotherapy, suggesting that restoring the expression of HtrA1 may be a promising treatment strategy for ovarian cancer.
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影响因子：
4
作者：
Chien, Jeremy;He, Xiaoping;Shridhar, Viji
通讯作者：
Shridhar, Viji
影响因子：
11.2
作者：
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通讯作者：
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DOI：
10.1016/j.ejogrb.2009.06.011
发表时间：
2009-10-01
影响因子：
2.6
作者：
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通讯作者：
Xin, Xiao-yan
影响因子：
4
作者：
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通讯作者：
Hartmann, Lynn C.
DOI：
10.1152/ajprenal.00154.2004
发表时间：
2005-02-01
影响因子：
4.2
作者：
Cilenti, L;Kyriazis, GA;Zervos, AS
通讯作者：
Zervos, AS