PAK1

Gene Summary

Gene:PAK1; p21 (RAC1) activated kinase 1
Aliases: PAKalpha
Location:11q13.5-q14.1
Summary:This gene encodes a family member of serine/threonine p21-activating kinases, known as PAK proteins. These proteins are critical effectors that link RhoGTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. This specific family member regulates cell motility and morphology. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:serine/threonine-protein kinase PAK 1
Source:NCBIAccessed: 09 March, 2017

Ontology:

What does this gene/protein do?
Show (44)
Pathways:What pathways are this gene/protein implicaed in?
Show (19)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Ovarian Cancer
  • Cell Movement
  • MicroRNAs
  • rho-Associated Kinases
  • Phosphorylation
  • Oligonucleotide Array Sequence Analysis
  • Chromosome 11
  • Western Blotting
  • Signal Transduction
  • Breast Cancer
  • Gene Amplification
  • rac GTP-Binding Proteins
  • Cell Proliferation
  • Neoplasm Invasiveness
  • Staging
  • Xenograft Models
  • Immunohistochemistry
  • Cancer Gene Expression Regulation
  • RHOA
  • Neurofibromatosis 2
  • Protein-Serine-Threonine Kinases
  • Neoplasm Proteins
  • Drug Resistance
  • Apoptosis
  • Gene Expression
  • Neoplastic Cell Transformation
  • RNA Interference
  • Gene Expression Profiling
  • Messenger RNA
  • PAK1 protein, human
  • Stomach Cancer
  • siRNA
  • Neoplasm Metastasis
  • Colorectal Cancer
  • p21-Activated Kinases
  • Mutation
  • RTPCR
  • Enzyme Activation
  • rho GTP-Binding Proteins
  • Transfection
Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PAK1 (cancer-related)

Kumar R, Sanawar R, Li X, Li F
Structure, biochemistry, and biology of PAK kinases.
Gene. 2017; 605:20-31 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
PAKs, p21-activated kinases, play central roles and act as converging junctions for discrete signals elicited on the cell surface and for a number of intracellular signaling cascades. PAKs phosphorylate a vast number of substrates and act by remodeling cytoskeleton, employing scaffolding, and relocating to distinct subcellular compartments. PAKs affect wide range of processes that are crucial to the cell from regulation of cell motility, survival, redox, metabolism, cell cycle, proliferation, transformation, stress, inflammation, to gene expression. Understandably, their dysregulation disrupts cellular homeostasis and severely impacts key cell functions, and many of those are implicated in a number of human diseases including cancers, neurological disorders, and cardiac disorders. Here we provide an overview of the members of the PAK family and their current status. We give special emphasis to PAK1 and PAK4, the prototypes of groups I and II, for their profound roles in cancer, the nervous system, and the heart. We also highlight other family members. We provide our perspective on the current advancements, their growing importance as strategic therapeutic targets, and our vision on the future of PAKs.

Li Y, Peng Y, Jiang X, et al.
Whole exome sequencing of thymic neuroendocrine tumor with ectopic ACTH syndrome.
Eur J Endocrinol. 2017; 176(2):187-194 [PubMed] Related Publications
OBJECTIVE: Thymic neuroendocrine tumor is the second-most prevalent cause of ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), which is a rare disease characterized by ectopic ACTH oversecretion from nonpituitary tumors. However, the genetic abnormalities of thymic neuroendocrine tumors with EAS remain largely unknown. We aim to elucidate the genetic abnormalities and identify the somatic mutations of potential tumor-related genes of thymic neuroendocrine tumors with EAS by whole exome sequencing.
DESIGN AND METHODS: Nine patients with thymic neuroendocrine tumors with EAS who were diagnosed at Shanghai Clinical Center for Endocrine and Metabolic Diseases in Ruijin Hospital between 2002 and 2014 were enrolled. We performed whole exome sequencing on the DNA obtained from thymic neuroendocrine tumors and matched peripheral blood using the Hiseq2000 platform.
RESULTS: We identified a total of 137 somatic mutations (median of 15.2 per tumor; range, 1-24) with 129 single-nucleotide mutations (SNVs). The predominant substitution in these mutations was C:G > T:A transition. Approximately 80% of detected mutations resulted in amino acid changes. However, we failed to discover any recurrent mutations in these nine patients. By functional predictions, HRAS, PAK1 and MEN1, previously reported in neuroendocrine tumors, were identified as candidate tumor-related genes associated with thymic neuroendocrine tumors.
CONCLUSIONS: Using whole exome sequencing, we identified genetic abnormalities in thymic neuroendocrine tumors with EAS. Thereby, this study acts as a further supplement of the genetic features of neuroendocrine tumors. Somatic mutations of three potential tumor-related genes (HRAS, PAK1 and MEN1) might contribute to the tumorigenesis of thymic neuroendocrine tumors with EAS.

Kim S, Jho EH
Merlin, a regulator of Hippo signaling, regulates Wnt/β-catenin signaling.
BMB Rep. 2016; 49(7):357-8 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Merlin, encoded by the NF2 gene, is a tumor suppressor that exerts its function via inhibiting mitogenic receptors at the plasma membrane. Although multiple mutations in Merlin have been identified in Neurofibromatosis type II (NF2) disease, its molecular mechanism is not fully understood. Here, we show that Merlin interacts with LRP6 and inhibits LRP6 phosphorylation, a critical step for the initiation of Wnt signaling. We found that treatment of Wnt3a caused phosphorylation of Merlin by PAK1, leading to detachment of Merlin from LRP6 and allowing the initiation of Wnt/β-catenin signaling. A higher level of β-catenin was found in tissues from NF2 patients. Enhanced proliferation and migration caused by knockdown of Merlin in glioblastoma cells were inhibited by suppression of β-catenin. Conclusively, these results suggest that sustained Wnt/β-catenin signaling activity induced by abrogation of Merlin-mediated inhibition of LRP6 phosphorylation might be a cause of NF2 disease. [BMB Reports 2016; 49(7): 357-358].

Mertins P, Mani DR, Ruggles KV, et al.
Proteogenomics connects somatic mutations to signalling in breast cancer.
Nature. 2016; 534(7605):55-62 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.

Jiao D, Zhang XD
Myricetin suppresses p21-activated kinase 1 in human breast cancer MCF-7 cells through downstream signaling of the β-catenin pathway.
Oncol Rep. 2016; 36(1):342-8 [PubMed] Related Publications
As a main active compound in the bark of waxberry (Myrica rubra), myricetin is a macrocyclic diarylheptanoid, and can trigger the apoptosis of HeLa and PC3 cells. The aim of the present study was to elucidate the anticancer effect of myricetin on human breast cancer MCF-7 cells and to explore the possible mechanisms of action. MCF-7 cells were treated with different concentrations of myricetin (0-80 µM) for 12, 24 and 48 h. In the present study, we found that myricetin suppressed the cell viability of the MCF-7 cells at least partly through the induction of apoptosis as determined by MTT assay and flow cytometry. Western blot analysis revealed that myricetin effectively suppressed the protein expression of p21-activated kinase 1 (PAK1), MEK and phosphorylated extracellular mitogen-activated protein kinase (ERK1/2). In addition, treatment of myricetin activated glycogen synthase kinase-3β (GSK3β) and Bax protein expression, and inhibited β-catenin/cyclin D1/proliferating cell nuclear antigen (PCNA)/survivin and promoted caspase-3 activity in the MCF-7 cells. These results demonstrated that myricetin suppressed the cell viability of human breast cancer MCF-7 cells through PAK1/MEK/ERK/GSK3β/β-catenin/cyclin D1/PCNA/survivin/Bax-caspase-3 signaling.

Yu C, Tang W, Wang Y, et al.
Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry.
Cancer Lett. 2016; 376(2):268-77 [PubMed] Related Publications
The renin-angiotensin system (RAS) is an important component of the tumor microenvironment and plays a key role in promoting cancer cell proliferation, angiogenesis, metabolism, migration and invasion. Meanwhile, the arm of angiotensin-converting enzyme (ACE)2/angiotensin-(1-7) [Ang-(1-7)]/Mas axis in connection with RAS is associated with anti-proliferative, vasodilatory and anti-metastatic properties. Previous studies have shown that Ang-(1-7) reduces the proliferation of orthotopic human breast tumor growth by inhibiting cancer-associated fibroblasts. However, the role of ACE/Ang-(1-7)/Mas axis in the metastasis of breast cancer cells is still unknown. In the present study, we found that ACE2 protein level is negatively correlated with the metastatic ability of breast cancer cells and breast tumor grade. Upregulation of ACE2/Ang-(1-7)/Mas axis inhibits breast cancer cell migration and invasion in vivo and in vitro. Mechanistically, ACE2/Ang-(1-7)/Mas axis activation inhibits store-operated calcium entry (SOCE) and PAK1/NF-κB/Snail1 pathways, and induces E-cadherin expression. In summary, our results demonstrate that downregulation of ACE2/Ang-(1-7)/Mas axis stimulates breast cancer metastasis through the activation of SOCE and PAK1/NF-κB/Snail1 pathways. These results provide new mechanisms by which breast cancer develop metastasis and shed light on developing novel anti-metastasis therapeutics for metastatic breast cancer by modulating ACE2/Ang-(1-7)/Mas axis.

Kumar R, Li DQ
PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology.
Adv Cancer Res. 2016; 130:137-209 [PubMed] Related Publications
Since the initial recognition of a mechanistic role of p21-activated kinase 1 (PAK1) in breast cancer invasion, PAK1 has emerged as one of the widely overexpressed or hyperactivated kinases in human cancer at-large, allowing the PAK family to make in-roads in cancer biology, tumorigenesis, and cancer therapeutics. Much of our current understanding of the PAK family in cancer progression relates to a central role of the PAK family in the integration of cancer-promoting signals from cell membrane receptors as well as function as a key nexus-modifier of complex, cytoplasmic signaling network. Another core aspect of PAK signaling that highlights its importance in cancer progression is through PAK's central role in the cross talk with signaling and interacting proteins, as well as PAK's position as a key player in the phosphorylation of effector substrates to engage downstream components that ultimately leads to the development cancerous phenotypes. Here we provide a comprehensive review of the recent advances in PAK cancer research and its downstream substrates in the context of invasion, nuclear signaling and localization, gene expression, and DNA damage response. We discuss how a deeper understanding of PAK1's pathobiology over the years has widened research interest to the PAK family and human cancer, and positioning the PAK family as a promising cancer therapeutic target either alone or in combination with other therapies. With many landmark findings and leaps in the progress of PAK cancer research since the infancy of this field nearly 20 years ago, we also discuss postulated advances in the coming decade as the PAK family continues to shape the future of oncobiology.

Lv D, Li L, Lu Q, et al.
PAK1-cofilin phosphorylation mediates human lung adenocarcinoma cells migration induced by apelin-13.
Clin Exp Pharmacol Physiol. 2016; 43(5):569-79 [PubMed] Related Publications
Adipocytokines apelin peptide, the ligand of APJ (putative receptor related to the angiotensin receptor AT1), plays key roles in the pathogenesis and deterioration of cancer. In lung cancer, apelin elevating microvessel densities has been reported. Our previous research has characterized that apelin-13 promoted lung adenocarcinoma cell proliferation. However, the effect of apelin on metastasis in lung adenocarcinoma and the underlying mechanisms remain unclear. This study shows that apelin-13 induced human adenocarcinoma cell migration via the APJ receptor. Apelin-13 phosphorylated PAK1 and cofilin increase the migration of lung adenocarcinoma cells. Moreover, the results verify that over-expression of apelin and APJ contributed to reducing the effect of doxorubicin and razoxane on inhibiting lung adenocarcinoma cells metastasis. Hypoxia activated APJ expression and apelin release in lung adenocarcinoma cells. The results demonstrate a PAK1-cofilin phosphorylation mechanism to mediate lung adenocarcinoma cells migration promoted by apelin-13. This discovery further suggests that APJ and its downstream signalling is a potential target for anti-metastatic therapies in lung adenocarcinoma patients.

Tang J, Guo YS, Yu XL, et al.
CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma.
Oncotarget. 2015; 6(33):34831-45 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC.

Belo H, Silva G, Cardoso BA, et al.
Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential.
PLoS One. 2015; 10(10):e0139740 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Fanconi anaemia (FA) is an inherited disorder characterized by chromosomal instability. The phenotype is variable, which raises the possibility that it may be affected by other factors, such as epigenetic modifications. These play an important role in oncogenesis and may be pharmacologically manipulated. Our aim was to explore whether the epigenetic profiles in FA differ from non-FA individuals and whether these could be manipulated to alter the disease phenotype. We compared expression of epigenetic genes and DNA methylation profile of tumour suppressor genes between FA and normal samples. FA samples exhibited decreased expression levels of genes involved in epigenetic regulation and hypomethylation in the promoter regions of tumour suppressor genes. Treatment of FA cells with histone deacetylase inhibitor Vorinostat increased the expression of DNM3Tβ and reduced the levels of CIITA and HDAC9, PAK1, USP16, all involved in different aspects of epigenetic and immune regulation. Given the ability of Vorinostat to modulate epigenetic genes in FA patients, we investigated its functional effects on the FA phenotype. This was assessed by incubating FA cells with Vorinostat and quantifying chromosomal breaks induced by DNA cross-linking agents. Treatment of FA cells with Vorinostat resulted in a significant reduction of aberrant cells (81% on average). Our results suggest that epigenetic mechanisms may play a role in oncogenesis in FA. Epigenetic agents may be helpful in improving the phenotype of FA patients, potentially reducing tumour incidence in this population.

Liu W, Liu Y, Liu H, et al.
Tumor Suppressive Function of p21-activated Kinase 6 in Hepatocellular Carcinoma.
J Biol Chem. 2015; 290(47):28489-501 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Our previous studies identified the oncogenic role of p21-activated kinase 1 (PAK1) in hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Contrarily, PAK6 was found to predict a favorable prognosis in RCC patients. Nevertheless, the ambiguous tumor suppressive function of PAK6 in hepatocarcinogenesis remains obscure. Herein, decreased PAK6 expression was found to be associated with tumor node metastasis stage progression and unfavorable overall survival in HCC patients. Additionally, overexpression and silence of PAK6 experiments showed that PAK6 inhibited xenografted tumor growth in vivo, and restricted cell proliferation, colony formation, migration, and invasion and promoted cell apoptosis and anoikis in vitro. Moreover, overexpression of kinase dead and nuclear localization signal deletion mutants of PAK6 experiments indicated the tumor suppressive function of PAK6 was partially dependent on its kinase activity and nuclear translocation. Furthermore, gain or loss of function in polycomb repressive complex 2 (PRC2) components, including EZH2, SUZ12, and EED, elucidated epigenetic control of H3K27me3-arbitrated PAK6 down-regulation in hepatoma cells. More importantly, negative correlation between PAK6 and EZH2 expression was observed in hepatoma tissues from HCC patients. These data identified the tumor suppressive role and potential underlying mechanism of PAK6 in hepatocarcinogenesis.

Kasap E, Gerceker E, Boyacıoglu SÖ, et al.
The potential role of the NEK6, AURKA, AURKB, and PAK1 genes in adenomatous colorectal polyps and colorectal adenocarcinoma.
Tumour Biol. 2016; 37(3):3071-80 [PubMed] Related Publications
Colorectal adenomatous polyp (CRAP) is a major risk factor for the development of sporadic colorectal cancer (CRC). Histone modifications are one of the epigenetic mechanisms that may have key roles in the carcinogenesis of CRC. The objective of the present study is to investigate the alternations in the defined histone modification gene expression profiles in patients with CRAP and CRC. Histone modification enzyme key gene expressions of the CRC, CRAP, and control groups were evaluated and compared using the reverse transcription PCR (RT-PCR) array method. Gene expression analysis was performed in the CRAP group after dividing the patients into subgroups according to the polyp diameter, pathological results, and morphological parameters which are risk factors for developing CRC in patients with CRAP. PAK1, NEK6, AURKA, AURKB, HDAC1, and HDAC7 were significantly more overexpressed in CRC subjects compared to the controls (p < 0.05). PAK1, NEK6, AURKA, AURKB, and HDAC1 were significantly more overexpressed in the CRAP group compared to the controls (p < 0.005). There were no significant differences between the CRAP and CRC groups with regards to PAK1, NEK6, AURKA, or AURKB gene overexpression. PAK1, NEK6, AURKA, and AURKB were significantly in correlation with the polyp diameter as they were more overexpressed in polyps with larger diameters. In conclusion, overexpressions of NEK6, AURKA, AURKB, and PAK1 genes can be used as predictive markers to decide the colonoscopic surveillance intervals after the polypectomy procedure especially in polyps with larger diameters.

Zheng M, Liu J, Zhu M, et al.
Potentially functional polymorphisms in PAK1 are associated with risk of lung cancer in a Chinese population.
Cancer Med. 2015; 4(11):1781-7 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
P21-activated kinase 1(PAK1) plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis and has been implicated with tumorigenesis and tumor progression. We hypothesized that functional polymorphisms in PAK1 gene may modify the risk of lung cancer. We screened four potentially functional polymorphisms (rs2154754, rs3015993, rs7109645, and rs2844337) in PAK1 gene and evaluated the association between the genetic variants and lung cancer risk in a case-control study including 1341 lung cancer cases and 1982 cancer-free controls in a Chinese population. We found that variant allele of rs2154754 was significantly associated with a decreased risk of lung cancer (OR = 0.85, 95% CI: 0.77-0.95, P = 0.004), meanwhile the result of rs3015993 was marginal (OR = 0.90, 95%CI: 0.81-1.00, P = 0.044). After multiple comparisons, rs2154754 was still significantly associated with the lung cancer risk (P < 0.0125 for Bonferroni correction). We also detected a significant interaction between rs2154754 genotypes and smoking levels on lung cancer risk (P = 0.042). Combined analysis of these two polymorphisms showed a significant allele-dosage association between the number of protective alleles and reduced risk of lung cancer (Ptrend = 0.008). These findings indicate that genetic variants in PAK1 gene may contribute to susceptibility to lung cancer in the Chinese population.

Gerçeker E, Boyacıoglu SO, Kasap E, et al.
Never in mitosis gene A-related kinase 6 and aurora kinase A: New gene biomarkers in the conversion from ulcerative colitis to colorectal cancer.
Oncol Rep. 2015; 34(4):1905-14 [PubMed] Related Publications
Ulcerative colitis (UC) is an important risk factor for colorectal cancer (CRC). Histone modifications are one of the epigenetic mechanisms that may have key roles in the carcinogenesis of CRC. At present, there are no studies comparing histone modification patterns of UC and CRC in the literature. Therefore the aim of the present study was to investigate whether genes, particularly those involved in histone modification, have value in patient monitoring with regards to CRC development in UC. Key gene expressions of the histone modification enzyme were assessed and compared in CRC, UC and control groups using the RT-PCR array technique. Patients were divided into subgroups based on the extent and duration of the disease and inflammatory burden, which are considered risk factors for CRC development in UC patients. In UC and CRC groups, a significantly higher overexpression of the NEK6 and AURKA genes compared to the control group was identified. In addition, there was a significantly higher overexpression of HDAC1 and PAK1 genes in the UC group, and of HDAC1, HDAC7, PAK1 and AURKB genes in the CRC group. NEK6, AURKA, HDAC1 and PAK1 were significantly overexpressed in patients with a longer UC duration. Overexpression of AURKA and NEK6 genes was significantly more pronounced in UC patients with more extensive colon involvement. HDAC1, HDAC7, PAK1, NEK6, AURKA and AURKB are important diagnostic and prognostic markers involved in the carcinogenesis of CRC. HDAC1, PAK1, NEK6 and AURKA may be considered as diagnostic markers to be used in CRC screening for UC patients.

Beauchamp RL, James MF, DeSouza PA, et al.
A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas.
Oncotarget. 2015; 6(19):16981-97 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Meningiomas are the most common primary intracranial adult tumor. All Neurofibromatosis 2 (NF2)-associated meningiomas and ~60% of sporadic meningiomas show loss of NF2 tumor suppressor protein. There are no effective medical therapies for progressive and recurrent meningiomas. Our previous work demonstrated aberrant activation of mTORC1 signaling that led to ongoing clinical trials with rapamycin analogs for NF2 and sporadic meningioma patients. Here we performed a high-throughput kinome screen to identify kinases responsible for mTORC1 pathway activation in NF2-deficient meningioma cells. Among the emerging top candidates were the mTORC2-specific target serum/glucocorticoid-regulated kinase 1 (SGK1) and p21-activated kinase 1 (PAK1). In NF2-deficient meningioma cells, inhibition of SGK1 rescues mTORC1 activation, and SGK1 activation is sensitive to dual mTORC1/2 inhibitor AZD2014, but not to rapamycin. PAK1 inhibition also leads to attenuated mTORC1 but not mTORC2 signaling, suggesting that mTORC2/SGK1 and Rac1/PAK1 pathways are independently responsible for mTORC1 activation in NF2-deficient meningiomas. Using CRISPR-Cas9 genome editing, we generated isogenic human arachnoidal cell lines (ACs), the origin cell type for meningiomas, expressing or lacking NF2. NF2-null CRISPR ACs recapitulate the signaling of NF2-deficient meningioma cells. Interestingly, we observe increased SGK1 transcription and protein expression in NF2-CRISPR ACs and in primary NF2-negative meningioma lines. Moreover, we demonstrate that the dual mTORC1/mTORC2 inhibitor, AZD2014 is superior to rapamycin and PAK inhibitor FRAX597 in blocking proliferation of meningioma cells. Importantly, AZD2014 is currently in use in several clinical trials of cancer. Therefore, we believe that AZD2014 may provide therapeutic advantage over rapalogs for recurrent and progressive meningiomas.

Pandolfi A, Stanley RF, Yu Y, et al.
PAK1 is a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome.
Blood. 2015; 126(9):1118-27 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Poor clinical outcome of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) has been attributed to failure of current chemotherapeutic regimens to target leukemic stem cells. We recently identified p21-activated kinase (PAK1) as a downstream effector molecule of H2.0-like homeobox (HLX), a gene functionally relevant for AML pathogenesis. In this study, we find that inhibition of PAK1 activity by small molecule inhibitors or by RNA interference leads to profound leukemia inhibitory effects both in vitro and in vivo. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of the MYC oncogene and a core network of MYC target genes. Importantly, we find that inhibition of PAK1 inhibits primary human leukemic cells including immature leukemic stem cell-enriched populations. Moreover, we find that PAK1 upregulation occurs during disease progression and is relevant for patient survival in MDS. Our studies highlight PAK1 as a novel target in AML and MDS and support the use of PAK1 inhibitors as a therapeutic strategy in these diseases.

Kim YB, Shin YJ, Roy A, Kim JH
The Role of the Pleckstrin Homology Domain-containing Protein CKIP-1 in Activation of p21-activated Kinase 1 (PAK1).
J Biol Chem. 2015; 290(34):21076-85 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Upon growth factor stimulation, PAK1 is recruited to the plasma membrane and activated by a mechanism that requires its phosphorylation at Ser-223 by the protein kinase CK2. However, the upstream signaling molecules that regulate this phosphorylation event are not clearly defined. Here, we demonstrate a major role of the CK2α-interacting protein CKIP-1 in activation of PAK1. CK2α, CKIP-1, and PAK1 are translocated to membrane ruffles in response to the epidermal growth factor (EGF), where CKIP-1 mediates the interaction between CK2α and PAK1 in a PI3K-dependent manner. Consistently, PAK1 mediates phosphorylation and modulation of the activity of p41-Arc, one of its plasma membrane substrate, in a fashion that requires PI3K and CKIP-1. Moreover, CKIP-1 knockdown or PI3K inhibition suppresses PAK1-mediated cell migration and invasion, demonstrating the physiological significance of the PI3K-CKIP-1-CK2-PAK1 signaling pathway. Taken together, these findings identify a novel mechanism for the activation of PAK1 at the plasma membrane, which is critical for cell migration and invasion.

Iyer SC, Gopal A, Halagowder D
Myricetin induces apoptosis by inhibiting P21 activated kinase 1 (PAK1) signaling cascade in hepatocellular carcinoma.
Mol Cell Biochem. 2015; 407(1-2):223-37 [PubMed] Related Publications
Hepatocellular carcinoma is one of the most common malignancies worldwide and evidence suggests that Ras signaling regulates various hallmarks of cancer via regulating several effector pathways such as ERK and PI3K. The aim of the present study is to understand the efficacy of a flavonoid myricetin for the first time in inhibiting the downstream target p21 activated kinase 1 (PAK1) of Ras signaling pathway in hepatocellular carcinoma. The analysis of gene expression revealed that myricetin inhibits PAK1 by abrogating the Ras-mediated signaling by decelerating Wnt signaling, the downstream of Erk/Akt, thereby inducing intrinsic caspase-mediated mitochondrial apoptosis by downregulating the expression of anti-apoptotic Bcl-2 and survivin and upregulating pro-apoptotic Bax. The results also provide striking evidence that the myricetin inhibits the development of HCC by inhibiting PAK1 via coordinate abrogation of MAPK/ERK and PI3K/AKT and their downstream signaling Wnt/β-catenin pathway, thus being a promising candidate for cancer prevention and therapy.

Senapedis W, Crochiere M, Baloglu E, Landesman Y
Therapeutic Potential of Targeting PAK Signaling.
Anticancer Agents Med Chem. 2016; 16(1):75-88 [PubMed] Related Publications
The therapeutic potential of targeting p21-Activated Kinases (PAK1 - 6) for the treatment of cancer has recently gained traction in the biotech industry. Many pharmaceutically-viable ATP competitive inhibitors have been through different stages of pre-clinical development with only a single compound evaluated in human trails (PF-3758309). The best studied functional roles of PAK proteins are control of cell adhesion and migration. PAK proteins are known downstream effectors of Ras signaling with PAK expression elevated in cancer (pancreatic, colon, breast, lung and other solid tumors). In addition altered PAK expression is a confirmed driver of this disease, especially in tumors harboring oncogenic Ras. However, there are very few examples of gain-of-function PAK mutations, as a majority of the cancer types have elevated PAK expression due to gene amplification or transcriptional modifications. There is a substantial number of known substrates affected by this aberrant PAK activity. One particular substrate, β-catenin, has garnered interest given its importance in both normal and cancer cell development. These data place PAK proteins between two major signaling pathways in cancer (Ras and β -catenin), making therapeutic targeting of PAKs an intriguing approach for the treatment of a broad array of oncological malignancies.

Gan J, Zhang Y, Ke X, et al.
Dysregulation of PAK1 Is Associated with DNA Damage and Is of Prognostic Importance in Primary Esophageal Small Cell Carcinoma.
Int J Mol Sci. 2015; 16(6):12035-50 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Primary esophageal small cell carcinoma (PESCC) is a rare, but fatal subtype of esophageal carcinoma. No effective therapeutic regimen for it. P21-activated kinase 1 (PAK1) is known to function as an integrator and an indispensable node of major growth factor signaling and the molecular therapy targeting PAK1 has been clinical in pipeline. We thus set to examine the expression and clinical impact of PAK1 in PESCC. The expression of PAK1 was detected in a semi-quantitative manner by performing immunohistochemistry. PAK1 was overexpressed in 22 of 34 PESCC tumors, but in only 2 of 18 adjacent non-cancerous tissues. Overexpression of PAK1 was significantly associated with tumor location (p = 0.011), lymph node metastasis (p = 0.026) and patient survival (p = 0.032). We also investigated the association of PAK1 with DNA damage, a driven cause for malignancy progression. γH2AX, a DNA damage marker, was detectable in 18 of 24 (75.0%) cases, and PAK1 expression was associated with γH2AX (p = 0.027). Together, PAK1 is important in metastasis and progression of PESCC. The contribution of PAK1 to clinical outcomes may be involved in its regulating DNA damage pathway. Further studies are worth determining the potentials of PAK1 as prognostic indicator and therapeutic target for PESCC.

Mortazavi F, Lu J, Phan R, et al.
Significance of KRAS/PAK1/Crk pathway in non-small cell lung cancer oncogenesis.
BMC Cancer. 2015; 15:381 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
BACKGROUND: Key effector(s) of mutated KRAS in lung cancer progression and metastasis are unknown. Here we investigated the role of PAK1/Crk axis in transduction of the oncogenic KRAS signal in non-small cell lung cancer (NSCLC).
METHODS: We used NSCLC clinical specimens to examine the correlation among KRAS mutations (codon 12, 13 and 61); PAK1/Crk axis activation [p-PAK1(Thr423), p-Crk(Ser41)]; and adhesion molecules expression by immunohistochemistry. For assessing the role of proto-oncogene c-Crk as a KRAS effector, we inhibited KRAS in NSCLC cells by a combination of farnesyltransferase inhibitor (FTI) and geranylgeranyltransferase inhibitor (GGTI) and measured p-Crk-II(Ser41) by western blotting. Finally, we disrupted the signaling network downstream of KRAS by blocking KRAS/PAK1/Crk axis with PAK1 inhibitors (i.e., IPA-3, FRAX597 or FRAX1036) along with partial inhibition of all other KRAS effectors by prenylation inhibitors (FTI + GGTI) and examined the motility, morphology and proliferation of the NSCLC cells.
RESULTS: Immunohistochemical analysis demonstrated an inverse correlation between PAK1/Crk phosphorylation and E-cadherin/p120-catenin expression. Furthermore, KRAS mutant tumors expressed higher p-PAK1(Thr423) compared to KRAS wild type. KRAS prenylation inhibition by (FTI + GGTI) completely dephosphorylated proto-oncogene c-Crk on Serine 41 while Crk phosphorylation did not change by individual prenylation inhibitors or diluent. Combination of PAK1 inhibition and partial inhibition of all other KRAS effectors by (FTI + GGTI) dramatically altered morphology, motility and proliferation of H157 and A549 cells.
CONCLUSIONS: Our data provide evidence that proto-oncogene c-Crk is operative downstream of KRAS in NSCLC. Previously we demonstrated that Crk receives oncogenic signals from PAK1. These data in conjunction with the work of others that have specified the role of PAK1 in transduction of KRAS signal bring forward the importance of KRAS/PAK1/Crk axis as a prominent pathway in the oncogenesis of KRAS mutant lung cancer.

Ong CC, Gierke S, Pitt C, et al.
Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents.
Breast Cancer Res. 2015; 17:59 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
INTRODUCTION: Breast cancer, the most common cause of cancer-related deaths worldwide among women, is a molecularly and clinically heterogeneous disease. Extensive genetic and epigenetic profiling of breast tumors has recently revealed novel putative driver genes, including p21-activated kinase (PAK)1. PAK1 is a serine/threonine kinase downstream of small GTP-binding proteins, Rac1 and Cdc42, and is an integral component of growth factor signaling networks and cellular functions fundamental to tumorigenesis.
METHODS: PAK1 dysregulation (copy number gain, mRNA and protein expression) was evaluated in two cohorts of breast cancer tissues (n=980 and 1,108). A novel small molecule inhibitor, FRAX1036, and RNA interference were used to examine PAK1 loss of function and combination with docetaxel in vitro. Mechanism of action for the therapeutic combination, both cellular and molecular, was assessed via time-lapse microscopy and immunoblotting.
RESULTS: We demonstrate that focal genomic amplification and overexpression of PAK1 are associated with poor clinical outcome in the luminal subtype of breast cancer (P=1.29×10(-4) and P=0.015, respectively). Given the role for PAK1 in regulating cytoskeletal organization, we hypothesized that combination of PAK1 inhibition with taxane treatment could be combined to further interfere with microtubule dynamics and cell survival. Consistent with this, administration of docetaxel with either a novel small molecule inhibitor of group I PAKs, FRAX1036, or PAK1 small interfering RNA oligonucleotides dramatically altered signaling to cytoskeletal-associated proteins, such as stathmin, and induced microtubule disorganization and cellular apoptosis. Live-cell imaging revealed that the duration of mitotic arrest mediated by docetaxel was significantly reduced in the presence of FRAX1036, and this was associated with increased kinetics of apoptosis.
CONCLUSIONS: Taken together, these findings further support PAK1 as a potential target in breast cancer and suggest combination with taxanes as a viable strategy to increase anti-tumor efficacy.

Liu W, Yue F, Zheng M, et al.
The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1.
Oncotarget. 2015; 6(11):8851-74 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor that plays a key role in regulating signaling pathways involved in mediating cancer cell invasion and migration, including those derived from prostate, colon, etc. However, the mechanisms and molecular targets through which NDRG1 reduces cancer cell invasion and migration, leading to inhibition of cancer metastasis, are not fully elucidated. In this investigation, using NDRG1 over-expression models in three tumor cell-types (namely, DU145, PC3MM and HT29) and also NDRG1 silencing in DU145 and HT29 cells, we reveal that NDRG1 decreases phosphorylation of a key proto-oncogene, cellular Src (c-Src), at a well-characterized activating site (Tyr416). NDRG1-mediated down-regulation of EGFR expression and activation were responsible for the decreased phosphorylation of c-Src (Tyr416). Indeed, NDRG1 prevented recruitment of c-Src to EGFR and c-Src activation. Moreover, NDRG1 suppressed Rac1 activity by modulating phosphorylation of a c-Src downstream effector, p130Cas, and its association with CrkII, which acts as a "molecular switch" to activate Rac1. NDRG1 also affected another signaling molecule involved in modulating Rac1 signaling, c-Abl, which then inhibited CrkII phosphorylation. Silencing NDRG1 increased cell migration relative to the control and inhibition of c-Src signaling using siRNA, or a pharmacological inhibitor (SU6656), prevented this increase. Hence, the role of NDRG1 in decreasing cell migration is, in part, due to its inhibition of c-Src activation. In addition, novel pharmacological agents, which induce NDRG1 expression and are currently under development as anti-metastatic agents, markedly increase NDRG1 and decrease c-Src activation. This study leads to important insights into the mechanism involved in inhibiting metastasis by NDRG1 and how to target these pathways with novel therapeutics.

Song B, Wang W, Zheng Y, et al.
P21-activated kinase 1 and 4 were associated with colorectal cancer metastasis and infiltration.
J Surg Res. 2015; 196(1):130-5 [PubMed] Related Publications
BACKGROUND: P21-activated kinases (PAKs) are small guanosine triphosphate effectors that play critical roles in many fundamental cellular functions, including cytoskeletal reorganization and cell motility. PAKs are widely expressed in a variety of tissues and are often overexpressed in multiple cancer types. The aim of this study was to investigate the relationship between PAK1 and PAK4 and clinicopathologic features of colorectal cancer.
METHODS: PAK1 and PAK4 expression in colorectal cancer patients were investigated via TaqMan real-time polymerase chain reaction and immunohistochemistry and clinical analysis.
RESULTS: The relative expression levels of PAK1 and PAK4 gene in colorectal carcinoma tissues were significantly higher than those in normal tissues (P < 0.01). PAK4 expression was higher than PAK1 in the same cancer tissue. The expression of PAK1 and PAK4 increased gradually with the clinical stages in carcinoma tissues (P < 0.01). PAK1 expression was higher in lymph node positive patients, and PAK4 expression was higher in infiltration into serous layer patients (P < 0.05). PAK1 overexpression group has a higher recurrence/metastasis rate compared with that of the PAK1 low expression group. Follow-up analysis showed that the median progression-free survival time of the PAK1 high expression group was significantly shorter than that of the PAK1 low expression group.
CONCLUSIONS: PAK1 and PAK4 expression were associated with colorectal cancer metastasis and infiltration, PAK1 high expression may indicate poor prognosis of colorectal cancer.

Wang G, Zhang Q, Song Y, et al.
PAK1 regulates RUFY3-mediated gastric cancer cell migration and invasion.
Cell Death Dis. 2015; 6:e1682 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Actin protrusion at the cell periphery is central to the formation of invadopodia during tumor cell migration and invasion. Although RUFY3 (RUN and FYVE domain containing 3)/SINGAR1 (single axon-related1)/RIPX (Rap2 interacting protein X) has an important role in neuronal development, its pathophysiologic role and relevance to cancer are still largely unknown. The purpose of this study was to elucidate the molecular mechanisms by which RUFY3 involves in gastric cancer cell migration and invasion. Here, our data show that overexpression of RUFY3 leads to the formation of F-actin-enriched protrusive structures at the cell periphery and induces gastric cancer cell migration. Furthermore, P21-activated kinase-1 (PAK1) interacts with RUFY3, and promotes RUFY3 expression and RUFY3-induced gastric cancer cell migration; inhibition of PAK1 attenuates RUFY3-induced SGC-7901 cell migration and invasion. Importantly, we found that the inhibitory effect of cell migration and invasion is significantly enhanced by knockdown of both PAK1 and RUFY3 compared with knockdown of RUFY3 alone or PAK1 alone. Strikingly, we found significant upregulation of RUFY3 in gastric cancer samples with invasive carcinoma at pathologic TNM III and TNM IV stages, compared with their non-tumor counterparts. Moreover, an obvious positive correlation was observed between the protein expression of RUFY3 and PAK1 in 40 pairs of gastric cancer samples. Therefore, these findings provide important evidence that PAK1 can positively regulate RUFY3 expression, which contribute to the metastatic potential of gastric cancer cells, maybe blocking PAK1-RUFY3 signaling would become a potential metastasis therapeutic strategy for gastric cancer.

Xiang J, Bian C, Wang H, et al.
MiR-203 down-regulates Rap1A and suppresses cell proliferation, adhesion and invasion in prostate cancer.
J Exp Clin Cancer Res. 2015; 34:8 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
OBJECTIVE: Evidence supports an important role for miR-203 in the regulation of the proliferation, migration and invasion of prostate cancer (PCa) cells. However, the exact mechanisms of miR-203 in PCa are not entirely clear.
METHODS: We examined the expression of miR-203 in prostate cancer tissues, adjacent normal tissues, PCa cell lines and normal prostate epithelial cells by qRT-PCR. Then, the effects of miR-203 or Rap1A on proliferation, adhesion and invasion of PCa cells were assayed using CKK-8, adhesion analysis, and transwell invasion assays. Luciferase reporter assay was performed to assess miR-203 binding to Rap1A mRNA. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice.
RESULTS: Here, we confirmed that the expression of miR-203 was significantly downregulated in prostate cancer specimens compared with matched adjacent normal prostate specimens. Mechanistic dissection revealed that miR-203 mediated cell proliferation, adhesion and invasion in vitro, and tumor growth in vivo, as evidenced by reduced RAC1, p-PAK1, and p-MEK1 expression. In addition, we identified Rap1A as a direct target suppressed by miR-203, and there was an inverse relationship between the expression of miR-203 and Rap1A in PCa. Knockdown of Rap1A phenocopied the effects of miR-203 on PCa cell growth and invasion. Furthermore, Rap1A over-expression in PCa cells partially reversed the effects of miR-203-expression on cell adhesion and invasion.
CONCLUSIONS: These findings provide further evidence that a crucial role for miR-203 in inhibiting metastasis of PCa through the suppression of Rap1A expression.

Chow HY, Dong B, Duron SG, et al.
Group I Paks as therapeutic targets in NF2-deficient meningioma.
Oncotarget. 2015; 6(4):1981-94 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of NF2 is found in 40-60% of sporadic meningiomas, but the molecular mechanisms underlying malignant changes of meningioma cells remain unclear. Because group I p21-activated kinases (Paks) bind to and are inhibited by the NF2-encoded protein Merlin, we assessed the signaling and anti-tumor effects of three group-I specific Pak inhibitors - Frax597, 716 and 1036 - in NF2-/- meningiomas in vitro and in an orthotopic mouse model. We found that these Pak inhibitors suppressed the proliferation and motility of both benign (Ben-Men1) and malignant (KT21-MG1) meningiomas cells. In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors. Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors. Similar effects were observed in Ben-Men1 cells. Tumors dissected from treated animals exhibited an increase in apoptosis without notable change in proliferation. Collectively, these results suggest that Pak inhibitors might be useful agents in treating NF2-deficient meningiomas.

Chatterjee A, Ghosh J, Ramdas B, et al.
Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis.
Cell Rep. 2014; 9(4):1333-48 [PubMed] Article available free on PMC after 20/03/2018 Related Publications
Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

Ergun S, Tayeb TS, Arslan A, et al.
The investigation of miR-221-3p and PAK1 gene expressions in breast cancer cell lines.
Gene. 2015; 555(2):377-81 [PubMed] Related Publications
The most common malignancy in women is breast cancer. Drug resistance in the treatment of cancer still remains a major clinical concern. Resistance to tamoxifen is seen in half of the recurrences in breast cancer. The anti-estrogen tamoxifen gains agonistic property by transactivating ERα. PAK1-mediated phosphorylation of serine 305 (S305) of ERα leads to resistance to tamoxifen. In our study, PAK1-induced suggestive tamoxifen resistance was designed. According to our hypothesis, phosphorylation of ERα-S305 by PAK1 may be reversed by PAK1 transcriptional inhibition by miR-221-3p due to miR-221-3p targeting the 3' UTR of PAK1. For this purpose, we used Real-time PCR (qRT-PCR) to measure the expression level of miR-221-3p in ER-positive breast cancer cell lines (ZR-75-1, MCF7) and breast epithelial cell line, hTERT-HME1, as control in the laboratory in our department. The increase in the expression of PAK1 depending on miR-221-3p may be related to ZR-75-1 cell line which has invasive characteristic but other two ER+ cancer cell lines, MCF7 and HCC1500, have milder cancer severity. miR-221-3p may have a role on regulation of PAK1 expression because miR-221-3p expression level decreases while PAK1 expression level increases in SKBR3 cell line. miR-221-3p and PAK1 expressions in MDA-MB-231 cell line are higher than that of hTERT-HME1 cell line. This may mean that miR-221-3p has no regulatory effect on of PAK1 expression in this cell line. According to these results, miR-221-3p may give crucial information about molecular mechanism of the disease upon PAK1 activity or different mechanisms with respect to histopathology and severity of breast cancer.

Huang K, Chen G, Luo J, et al.
Clinicopathological and cellular signature of PAK1 in human bladder cancer.
Tumour Biol. 2015; 36(4):2359-68 [PubMed] Related Publications
Bladder cancer (BC) is the ninth most common cancer and the 13th most common cause of cancer death. Although p21 protein-activated kinase (PAK) regulates cell growth, motility, and morphology, the expression and function of PAK1 associated with the clinicopathological and cellular signature of human BC are not clear. This study was to examine the expression of PAK1 in human BC, the association of PAK1 with clinicopathological features, and the effect of PAK1 on cell proliferation, migration, and invasion in BC cells. A total of 54 BC and 12 normal bladder tissue specimens were retrieved. Among 54 BC patients, 39 cases were superficial BC and 15 cases were invasive BC. Histological examination revealed 29 patients with low-grade and 25 patients with high-grade papillary urothelial carcinomas. Immunohistochemical staining showed that PAK1 was overexpressed in BC tissue compared with normal bladder tissue. The overexpression of PAK1 was significantly associated with tumor size, histological grade, and lymph node metastasis, but not with gender, age, clinical stage, tumor number, and recurrence. Furthermore, the cytoplasmic distribution of PAK1 was observed in BC cells. Knocking down of PAK1 using lentiviral transduction decreased BC cell proliferation, migration, and invasion. In conclusion, we demonstrated that the overexpression of PAK1 is closely associated with the clinicopathological features of BC, suggesting that PAK1 may play an important role in the development and progression of BC and may be a potential therapeutic target for the treatment of BC.

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