Tissue transglutaminase protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting cell survival signaling
Tissue transglutaminase protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting cell survival signaling
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DOI：
10.1093/carcin/bgn158
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发表时间：
2008-10-01
期刊：
影响因子：
4.7
通讯作者：
Matei, Daniela
中科院分区：
文献类型：
--
作者：
Cao, Liyun;Petrusca, Daniela N.;Matei, Daniela
组织转谷氨酰胺酶 (TG2) 是一种参与蛋白质交联并在卵巢肿瘤中过度表达的酶，对癌细胞具有抗凋亡作用，并可能在化疗反应中发挥作用。在本研究中，我们研究了TG2在卵巢癌细胞对顺铂敏感性中的作用。通过使用稳定敲低和过表达策略，我们证明TG2的表达水平调节顺铂诱导的SKOV3和OV-90卵巢癌细胞的细胞凋亡。有趣的是，不仅TG2敲低，TG2酶抑制剂（KCC009）也使SKOV3细胞对顺铂敏感。为了了解 TG2 发挥抗凋亡作用的机制，我们检查了蛋白激酶 B (Akt) 和核因子 kappa B (NF-kappa B) 这两种通常参与耐药性发展的生存途径的作用。 NF-kappa B 的组成型活性 p65 亚基的过表达，而非组成型活性的 Akt，可将 TG2 表达减少的细胞从顺铂诱导的细胞凋亡中拯救出来。这表明 NF-κ B 的激活是 TG2 下游的主要顺铂耐药机制。事实上，在经过工程改造、表达降低的 TG2 水平或用酶抑制剂 KCC009 处理的卵巢癌细胞中，NF-κ B 活性降低，抑制性亚基 I kappa B α 水平升高。我们的数据表明，TG2 通过激活卵巢癌细胞中的 NF-kappa B 存活途径来防止顺铂诱导的细胞凋亡。
Tissue transglutaminase (TG2), an enzyme involved in protein cross-linking and overexpressed in ovarian tumors, has antiapoptotic effects in cancer cells and may play a role in response to chemotherapy. In this study, we investigated the role of TG2 in the sensitivity of ovarian cancer cells to cisplatin. By using stable knockdown and overexpression strategies, we demonstrate that the level of expression of TG2 regulates apoptosis induced by cisplatin in SKOV3 and OV-90 ovarian cancer cells. Interestingly, not onlyTG2knockdownbut also a TG2 enzymatic inhibitor(KCC009) sensitized SKOV3 cells to cisplatin. To understand the mechanism by which TG2 exerts its antiapoptotic role, we examined the effects of protein kinase B (Akt) and nuclear factor-kappa B (NF-kappa B), two survival pathways commonly involved in development of drug resistance. Overexpression of the constitutively active p65 subunit of NF-kappa B, but not constitutively active Akt, rescued cells with diminished TG2 expression from cisplatin-induced apoptosis. This implicates activation of NF-kappa B as the main cisplatin resistance mechanism downstream of TG2. Indeed, NF-kappa B activity is decreased and the level of the inhibitory subunit I kappa B alpha is increased in ovarian cancer cells engineered to express diminished levels of TG2 or treated with the enzymatic inhibitor, KCC009. Our data show that TG2 prevents apoptosis induced by cisplatin by activating the NF-kappa B survival pathway in ovarian cancer cells.