Abstract
The p21-activated kinases (PAKs) are downstream effectors of the Rho family small GTPases as well as a wide variety of mitogenic factors and have been implicated in cancer formation, development and metastasis. PAKs phosphorylate a wide spectrum of substrates to mediate extracellular signals and regulate cytoskeletal remodeling, cell motility and survival. In this review, we aim to summarize the findings regarding the oncogenic role and the underlying mechanisms of PAKs signaling in various cancers, and in particular highlight the prime importance of PAKs in hepatocellular carcinoma (HCC) progression and metastasis. Recent studies exploring the potential therapeutic application of PAK inhibitors will also be discussed.
Highlights
Liver cancer is the fifth most common cancer in the world and prevalent in Eastern Asia including China, Taiwan, Korea and Japan [1,2]
Other than upregulating PAK1, hyperactivity of small GTPases Rac3 was found to augment the kinase activity of PAK1 in breast cancer [65]. These findings provided compelling evidences that PAK1 is critical in breast cancer progression and metastasis
PAK1 overexpression was frequently observed in hepatocellular carcinoma (HCC) and significantly associated with more aggressive and metastatic tumor phenotypes as well as advanced tumor stage
Summary
Liver cancer (hepatocellular carcinoma, HCC) is the fifth most common cancer in the world and prevalent in Eastern Asia including China, Taiwan, Korea and Japan [1,2]. In a diethylnitrosamine (DEN)induced liver carcinogenesis animal model, PAK1 overexpression was observed along HCC progression, together with the upregulation of cyclin D1 and activation of ERK1/2, p38 as well as JNK1/2 kinases [68], strongly suggesting its contribution in HCC development and progression. Our recent study has shown that IPA3 suppressed the growth of HCC tumor in nude mouse, blocked the activation of NF-κB via PAK1 inhibition and attenuated the survival signal of HCC cells [69]. The pyrrolopyrazole inhibitor PF-3758309, which was isolated from a high-throughput screening of molecules that inhibit both Group I and II PAKs activity, has been shown to suppress in vivo cancer cell growth [83]. PAKs converge the extracellular signals, interact and phosphorylate pools of intracellular substrates, resulting in the promotion of cancer cell survival and invasiveness. Authors’ contributions Both authors reviewed the literature in this review, drafted, prepared approved the manuscript
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