由意大利Carlo Gambacorti-Passerini教授领导的米兰San Gerardo 医院的研究小组近日发现了一个形成结肠癌的关键机制，即Beta-catenin蛋白是如何改变自身结构，渗透到健康的细胞中去，并将这些健康的细胞转变成癌的。
研究人员发现了可诱发Beta-catenin蛋白变异的名为SRC的第二蛋白，此前人们尚不知这个过程究竟是如何发生的。目前已有药物能够阻止SRC的活动，因此未来可以有药物用来治疗这种肿瘤。Carlo Gambacorti教授认为他们的研究会对临床诊治起很大作用。该研究发表在著名的《癌症研究》杂志上。
Inhibition of deregulated protein tyrosine kinases represents an attractive strategy for controlling cancer growth. However, target specificity is an essential aim of this strategy. In this report, pp60(c-Src) kinase and beta-catenin were found physically associated and constitutively activated on tyrosine residues in human colorectal cancer cells. The use of specific small-interfering RNAs (siRNA) validated pp60(c-Src) as the major kinase responsible for beta-catenin tyrosine phosphorylation in colorectal cancer. Src-dependent activation of beta-catenin was prevented by SKI-606, a novel Src family kinase inhibitor, which also abrogated beta-catenin nuclear function by impairing its binding to the TCF4 transcription factor and its trans-activating ability in colorectal cancer cells. These effects were seemingly specific, as cyclin D1, a crucial beta-catenin/TCF4 target gene, was also down-regulated by SKI-606 in a dose-dependent manner accounting, at least in part, for the reduced growth (IC50, 1.5-2.4 micromol/L) and clonogenic potential of colorectal cancer cells. Protein levels of beta-catenin remained substantially unchanged by SKI-606, which promoted instead a cytosolic/membranous retention of beta-catenin as judged by immunoblotting analysis of cytosolic/nuclear extracts and cell immunofluorescence staining. The SKI-606-mediated relocalization of beta-catenin increased its binding affinity to E-cadherin and adhesion of colorectal cancer cells, with ensuing reduced motility in a wound healing assay. Interestingly, the siRNA-driven knockdown of beta-catenin removed the effect of SKI-606 on cell-to-cell adhesion, which was associated with prolonged stability of E-cadherin protein in a pulse-chase experiment. Thus, our results show that SKI-606 operates a switch between the transcriptional and adhesive function of beta-catenin by inhibiting its pp60(c-Src)-dependent tyrosine phosphorylation; this could constitute a new therapeutic target in colorectal cancer.
原始出处：
Coluccia AM, Benati D, Dekhil H, De Filippo A, Lan C, Gambacorti-Passerini C.
SKI-606 decreases growth and motility of colorectal cancer cells by preventing pp60(c-Src)-dependent tyrosine phosphorylation of beta-catenin and its nuclear signaling. Cancer Res. 2006 Feb 15;66(4):2279-86.
有关信号通路研究：
βeta-catenin Pathway Inhibitors
Several proteins within the beta-catenin pathway play key roles in the initiation and progression of cancer. For example, it has been estimated that the beta-catenin pathway is abnormally activated in more than 85% of colon cancer.
Using AvalonRx we have identified structurally distinct compounds that appear to affect the beta-catenin pathway. We have used a gene expression signature that indicates decreased beta-catenin activity as a tool to identify nine active compound families from our library that appear to inhibit the beta-catenin pathway.
We have initiated medicinal chemistry efforts in lead optimization around one of the active compound families identified from this effort and we expect to initiate similar efforts on other active compound families. We have used AvalonRx to demonstrate that specific analogs can slow the growth of tumors in tumor xenograft models in animals.
