Wnt/β-catenin signaling pathway as novel cancer drug targets

被引:205
作者
Luu, HH
Zhang, RW
Haydon, RC
Rayburn, E
Kang, Q
Si, WK
Park, JK
Wang, H
Peng, Y
Jiang, W
He, TC
机构
[1] Univ Chicago, Ctr Med, Dept Surg, Mol Oncol Lab, Chicago, IL 60637 USA
[2] Univ Alabama Birmingham, Dept Pharmacol & Toxicol, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA
[4] Chongqing Univ Med Sci, Childrens Hosp, Chongqing 400016, Peoples R China
[5] Third Mil Med Univ, Dept Clin Biochem, Chongqing 400038, Peoples R China
[6] Catholic Univ Korea, Coll Med, St Pauls Hosp, Dept Surg, Seoul, South Korea
关键词
Wnt; beta-catenin; signal transduction; tumorigenesis; cancer targets; high throughput screening;
D O I
10.2174/1568009043332709
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Writ proteins are a large family of secreted glycoproteins. Writ proteins bind to the Frizzled receptors and LRP5/6 co-receptors, and through stabilizing the critical mediator beta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation. Deregulation of the canonical Wnt/beta-catenin signaling pathway, mostly by inactivating mutations of the APC tumor suppressor, or oncogenic mutations of beta-catenin, has been implicated in colorectal tumorigenesis. Although oncogenic mutations of beta-catenin have only been discovered in a small fraction of non-colon cancers, elevated levels of beta-catenin protein, a hallmark of activated canonical Writ pathway, have been observed in most common forms of human malignancies, indicating that activation of this pathway may play an important role in tumor development. Over the past 15 years, our understanding of this signaling pathway has significantly improved with the identification of key regulatory proteins and the important downstream targets of beta-catenin/Tcf transactivation complex. Given the fact that Wnt/beta-catenin signaling is tightly regulated at multiple cellular levels, the pathway itself offers ample targeting nodal points for cancer drug development. In this review, we discuss some of the strategies that are being used or can be explored to target key components of the Wnt/beta-catenin signaling pathway in rational cancer drug discovery.
引用
收藏
页码:653 / 671
页数:19
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