Molecular pathways: targeting p21-activated kinase 1 signaling in cancer--opportunities, challenges, and limitations.
Molecular pathways: targeting p21-activated kinase 1 signaling in cancer--opportunities, challenges, and limitations.
复制标题
DOI：
10.1158/1078-0432.ccr-11-1952
复制
发表时间：
2012-07-15
期刊：
影响因子：
--
通讯作者：
Kumar R
中科院分区：
文献类型：
--
作者：
Eswaran J;Li DQ;Shah A;Kumar R
癌细胞的演变涉及对正常细胞结构和功能至关重要的高度调节的基本途径的失调。p21激活激酶1（PAK1）最初被鉴定为GTP酶Rac和Cdc42的下游效应子。随后的研究发现了其在生长因子和类固醇受体信号传导、细胞骨架重塑、细胞存活、致癌转化和基因转录中的大量新功能，主要是通过系统地发现其直接的生理相关底物。PAK1在几种人类癌症中广泛上调，包括肿瘤依赖性癌症，并且与肿瘤进展和治疗抗性密切相关。这些令人兴奋的发展与PAK1在癌细胞中以表型信号传导为中心的激酶非依赖性作用相结合，使PAK1成为一个有吸引力的药物靶点。结构和生化研究揭示了PAK1激活的确切机制，为开发PAK1靶向癌症治疗方法提供了可能性。此外，新出现的报告表明PAK1及其特异性磷酸化底物作为癌症预后标志物的潜力。在此，我们总结了PAK1在人类癌症中的分子通路，并讨论了PAK1靶向抗癌治疗的现状。
The evolution of cancer cells involves deregulation of highly regulated fundamental pathways that are central to normal cellular architecture and functions. The p21-activated kinase 1 (PAK1) was initially identified as a downstream effector of the GTPases Rac and Cdc42. Subsequent studies uncovered a plethora of its new functions in growth factor and steroid receptor signaling, cytoskeleton remodeling, cell survival, oncogenic transformation, and gene transcription, largely through systematic discovery of its direct, physiologically relevant substrates. PAK1 is widely up-regulated in several human cancers including hormone-dependent cancer, and is intimately linked to tumor progression and therapeutic resistance. These exciting developments combined with the kinase-independent role of PAK1-centered phenotypic signaling in cancer cells elevated PAK1 as an attractive drug target. The structural and biochemical studies revealed the precise mechanism of PAK1 activation, offering the possibilities to develop PAK1-targeted cancer therapeutic approaches. In addition, emerging reports suggest the potential of PAK1 and its specific phosphorylated substrates as cancer prognostic markers. Here, we summarize the PAK1 molecular pathways in human cancer and discuss the current status of PAK1 targeted anti-cancer therapies.