The Tumor Suppressor, p190RhoGAP, Differentially Initiates Apoptosis and Confers Docetaxel Sensitivity to Breast Cancer Cells.
The Tumor Suppressor, p190RhoGAP, Differentially Initiates Apoptosis and Confers Docetaxel Sensitivity to Breast Cancer Cells.
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DOI：
10.1177/1947601911402680
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发表时间：
2011-01-01
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影响因子：
--
通讯作者：
Parsons, Sarah J
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作者：
Ludwig, Kirsten;Parsons, Sarah J
p190RhoGAP （p190）是rhogtpase的负调控因子，是一种推定的肿瘤抑制因子，其抑瘤机制尚不明确。p190的异位表达诱导多种形态表型，包括多核、树突样形成和染色质凝聚，提示其参与细胞凋亡。我们研究了p190通过调节诱导细胞凋亡作为肿瘤抑制因子的可能性。我们发现p190在多种细胞系中过表达的主要表型是凋亡，这是通过p190调节Rho和caspases介导的。次级表型，多核和树突样的形成，是由转化状态决定的，而不是由细胞谱系决定的，它们似乎是p190诱导的凋亡途径中的中间表型。最后，我们发现p190水平可以通过调控Rho调节乳腺癌细胞株对多西紫杉醇的凋亡反应。总之，这些发现表明p190介导其肿瘤抑制功能的一种机制是通过调节rho激活的细胞死亡途径，并且可以利用这种功能来优化基于细胞骨架的化疗药物的作用，如紫杉烷。
p190RhoGAP (p190) is a negative regulator of RhoGTPases and a putative tumor suppressor, whose mechanism of tumor suppression is poorly defined. Ectopic expression of p190 induces various morphological phenotypes, including multinucleation, dendrite-like formation, and chromatin condensation, suggesting an involvement in apoptosis. We examined the possibility that p190 can function as a tumor suppressor by regulating induction of apoptosis. We show that the predominant phenotype of p190 overexpression in a variety of cell lines is apoptosis, which is mediated through p190's regulation of Rho and caspases. The secondary phenotypes, multinucleation and dendrite-like formation, are determined by transformation status, not cell lineage, and appear to be intermediate phenotypes in the p190-induced apoptotic pathway. Finally, we show that p190 levels can regulate the apoptotic response of breast cancer cell lines to docetaxel through its regulation of Rho. Together, these findings suggest that one mechanism by which p190 can mediate its tumor-suppressive function is through regulation of Rho-activated cell death pathways and that this function can be exploited to optimize the action of cytoskeletal-based chemotherapeutics, such as the taxanes.