Tripathi Veenu, Popescu Nicholas C, Zimonjic Drazen B
Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, 37 Convent Drive, MSC 4262, Bethesda, Maryland 20892 USA.
Springerplus. 2014 Jan 14;3:27. doi: 10.1186/2193-1801-3-27. eCollection 2014.
DLC1 (Deleted in Liver Cancer 1) gene encodes a RhoGTPase-activating protein (RhoGAP), which exerts most of its tumor suppressor functions through suppression of small Rho GTPases proteins RhoA, RhoB, RhoC and to some degree Cdc42, but not Rac. RhoGTPases are implicated in NF-κB activation in highly invasive prostate carcinoma (PCA), with consequences on cell proliferation, survival and metastatic capacity. Here we demonstrate that DLC1 transduction in two androgen-independent (AI) and highly metastatic PCA cell lines negatively regulates NF-κB activity in a GAP- and α-catenin-dependent manner. Expressed DLC1 protein suppresses the phosphorylation of NF-κB inhibitor, IκBα, causes its relocation from membrane ruffles into cytoplasm and attenuates its ubiquitination and subsequent degradation. DLC1-mediated NF-kB suppression and its effects are comparable to NF-κB inhibition using either shRNA knockdown or peptide inhibitor. Expression of transduced DLC1 suppressed the expression of NF-κB mediated genes. Such effects were found to be reliant on presence of calcium, indicating that the observed modifications are dependent on, and enabled by DLC-mediated stabilization of adherens junctions. These results expand the multitude of DLC1 interactions with other genes that modulate its oncosuppressive function, and may have potential therapeutic implications.
肝癌缺失基因1（DLC1）编码一种RhoGTP酶激活蛋白（RhoGAP），该蛋白主要通过抑制小Rho GTP酶蛋白RhoA、RhoB、RhoC以及在一定程度上抑制Cdc42（而非Rac）来发挥其肿瘤抑制功能。RhoGTP酶与高侵袭性前列腺癌（PCA）中的核因子κB（NF-κB）激活有关，对细胞增殖、存活和转移能力产生影响。在此，我们证明在两种雄激素非依赖性（AI）且高转移性的PCA细胞系中导入DLC1以一种依赖GAP和α连环蛋白的方式负向调节NF-κB活性。表达的DLC1蛋白抑制NF-κB抑制剂IκBα的磷酸化，使其从膜皱褶重新定位到细胞质中，并减弱其泛素化及随后的降解。DLC1介导的NF-κB抑制及其作用与使用短发夹RNA（shRNA）敲低或肽抑制剂抑制NF-κB的效果相当。导入的DLC1的表达抑制了NF-κB介导的基因的表达。发现这些作用依赖于钙的存在，表明观察到的修饰依赖于并由DLC介导的黏附连接的稳定作用所促成。这些结果扩展了DLC1与其他调节其抑癌功能的基因之间的多种相互作用，并且可能具有潜在的治疗意义。
