P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer

Abstract

The p21-Activated kinase 1 (PAK1), a member of serine-threonine kinases family, was initially identified as an interactor of the Rho GTPases RAC1 and CDC42, which affect a wide range of processes associated with cell motility, survival, metabolism, cell cycle, proliferation, transformation, stress, inflammation, and gene expression. Recently, the PAK1 has emerged as a potential therapeutic target in cancer due to its role in many oncogenic signaling pathways. Many PAK1 inhibitors have been developed as potential preclinical agents for cancer therapy. Here, we provide an overview of essential roles that PAK1 plays in cancer, including its structure and autoactivation mechanism, its crucial function from onset to progression to metastasis, metabolism, immune escape and even drug resistance in cancer; endogenous regulators; and cancer-related pathways. We also summarize the reported PAK1 small-molecule inhibitors based on their structure types and their potential application in cancer. In addition, we provide overviews on current progress and future challenges of PAK1 in cancer, hoping to provide new ideas for the diagnosis and treatment of cancer.

RHOV promotes lung adenocarcinoma cell growth and metastasis through JNK/c-Jun pathway

“…RHOV is a member of the Rho GTPase family, and plays a vital role in neurodevelopment and embryogenesis [19,20]. RHOV have been identified to activate p21-activated kinases (Paks) [9,21], which affect a wide range of physiological and pathological processes [22]. However, the biological function of RHOV in human cancer is unclear.…”

Overexpression of microRNA-19a-3p promotes lymph node metastasis of esophageal squamous cell carcinoma via the RAC1/ CDC42-PAK1 pathway

“…In many cancers, upstream molecules are often via activating RAC1 and CDC42 to regulate downstream effector proteins to exert their biological functions, including cell migration (27)(28)(29). PAK1 is a serine/threonine protein kinase that has a crucial role in various signaling pathways and often acts as downstream effector of the small GTPases CDC42 and RAC1 (30). CDC42 and RAC1 bind to PAK1, causing a conformational transform and the subsequent autophosphorylation of several serine and/or threonine residues, which activates PAK1 to exert its biological functions including cell migration (30) The migratory ratios in two cell lines after lentiviral vector transfection.…”

“…PAK1 is a serine/threonine protein kinase that has a crucial role in various signaling pathways and often acts as downstream effector of the small GTPases CDC42 and RAC1 (30). CDC42 and RAC1 bind to PAK1, causing a conformational transform and the subsequent autophosphorylation of several serine and/or threonine residues, which activates PAK1 to exert its biological functions including cell migration (30) The migratory ratios in two cell lines after lentiviral vector transfection. The results show that the migratory ratio was higher in the NC (negative control sequence transfection) group than in the KD (miR-19a-3p-inhibition sequence transfection) group in KYSE-150 and TE-1 facilitating angiogenesis via VEGF-mediated Raf-1 and MEK1 activation during angiogenesis (31), promoting tumor epithelial-mesenchymal transformation (EMT) by upregulating the expression of matrix metalloproteinase and activating various transcription factors (32,33), and regulating the cytoskeleton remodeling process to promote cell migration (34).…”

The Role of p21-Activated Kinases in Cancer and Beyond: Where Are We Heading?

“…It is reported that PAK1 inhibition leads to decreased mTOR activity and cytostatic autophagy, and regulation of PAK1 in other cascades (MAPK and NF-κB) can indirectly regulate autophagy ( Dou et al, 2016 ; Wang et al, 2016 , 2017 ). The loss of epithelial cell integrity resulting from degradation of the adhesive connections, which maintain contact between epithelial cells, is a hallmark of EMT, which is mainly accomplished by EMT promoting transcription factors (twist, snail, and slug) via PAK-activated signaling pathways, such as MAPK, PI3K/AKT, NF-κB, LIMK1/cofilin, and JNK signaling pathways ( Yao et al, 2020 ). The cross-talk of PAKs with other signaling pathways is critical for cancer progression.…”