Evidence that GTP-binding domain but not catalytic domain of transglutaminase 2 is essential for epithelial-to-mesenchymal transition in mammary epithelial cells.
Evidence that GTP-binding domain but not catalytic domain of transglutaminase 2 is essential for epithelial-to-mesenchymal transition in mammary epithelial cells.
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DOI：
10.1186/bcr3085
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发表时间：
2012-01-06
期刊：
影响因子：
--
通讯作者：
Mehta K
中科院分区：
文献类型：
--
作者：
Kumar A;Xu J;Sung B;Kumar S;Yu D;Aggarwal BB;Mehta K
促炎蛋白组织转氨酶2（TG 2）的表达在多种癌细胞类型中经常上调。然而，TG 2在癌细胞中的确切作用还不清楚。我们最近启动了研究，以确定TG 2在癌细胞中的意义，并观察到TG 2的持续表达导致上皮间质转化（EMT），并促进乳腺上皮细胞中的癌症干细胞（CSC）性状。这些结果表明，TG 2可以作为一个有前途的治疗靶点，用于克服化疗耐药性和抑制癌细胞的转移扩散。使用各种突变体构建体，我们分析了TG 2的活性，其对于促进EMT-CSC表型是必需的。我们的研究结果表明，无催化活性的TG 2（TG 2-C277 S）在诱导乳腺上皮细胞中的EMT-CSC方面与野生型TG 2（TG 2-WT）一样有效。相反，过度表达的GTP结合缺陷型突变体（TG 2-R580 A）在这方面是完全没有能力的。此外，促炎性转录因子NF-κB的TG 2依赖性活化被认为是促进乳腺上皮细胞中EMT-CSC表型的必要条件。我们的研究结果表明，TG 2的转酰胺活性不是促进其致癌功能所必需的，并为开发小分子抑制剂以阻断TG 2的GTP结合口袋提供了强有力的理论基础。此类抑制剂可能具有抑制TG 2调节的途径、逆转耐药性和抑制癌细胞转移的巨大潜力。
The expression of proinflammatory protein tissue transglutaminase 2 (TG2) is frequently upregulated in multiple cancer cell types. However, the exact role of TG2 in cancer cells is not well-understood. We recently initiated studies to determine the significance of TG2 in cancer cells and observed that sustained expression of TG2 resulted in epithelial-to-mesenchymal transition (EMT) and promoted cancer stem cell (CSC) traits in mammary epithelial cells. These results suggested that TG2 could serve as a promising therapeutic target for overcoming chemoresistance and inhibiting metastatic spread of cancer cells. Using various mutant constructs, we analyzed the activity of TG2 that is essential for promoting the EMT-CSC phenotype. Our results suggest that catalytically inactive TG2 (TG2-C277S) is as effective as wild-type TG2 (TG2-WT) in inducing the EMT-CSC in mammary epithelial cells. In contrast, overexpression of a GTP-binding-deficient mutant (TG2-R580A) was completely incompetent in this regard. Moreover, TG2-dependent activation of the proinflammatory transcription factor NF-κB is deemed essential for promoting the EMT-CSC phenotype in mammary epithelial cells. Our results suggest that the transamidation activity of TG2 is not essential for promoting its oncogenic functions and provide a strong rationale for developing small-molecule inhibitors to block GTP-binding pockets of TG2. Such inhibitors may have great potential for inhibiting the TG2-regulated pathways, reversing drug resistance and inhibiting the metastasis of cancer cells.
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