p21-activated kinase signaling in breast cancer

The p21-activated kinases signal through a number of cellular pathways fundamental to growth, differentiation and apoptosis. A wealth of information has accumulated at an impressive pace in the recent past, both with regard to previously identified targets for p21-activated kinases that regulate the actin cytoskeleton and cellular stress pathways and with regard to newly identified targets and their role in cancer. Emerging data also provide new clues towards a previously unappreciated link between these various cellular processes. The present review attempts to provide a quick tutorial to the reader about the evolving significance of p21-activated kinases and small GTPases in breast cancer, using information from mouse models, tissue culture studies, and human materials.     

Nuclear p21-activated kinase 1 in breast cancer packs off tamoxifen sensitivity

There is significant clinical interest in the factors that influence the development of tamoxifen resistance in estrogen receptor-alpha (ER-alpha)-positive breast cancers. Recent studies suggest that in ER-positive breast tumor cells, elevated protein levels, and in particular, nuclear localization of p21-activated kinase 1 (PAK1), is associated with the progressive limitation of tamoxifen sensitivity. These phenotypic effects of PAK1 in model systems are mechanistically linked with the ability of PAK1 to phosphorylate ER-alpha on serine 305 and subsequent secondary activation of serine 118. These findings prompt further investigation of how nuclear signaling by PAK1 may affect estrogen's action and whether tamoxifen resistance might be prevented or reversed by PAK1 inhibition.     

P21-activated kinase 1 and breast cancer

<正>The p21-activated kinase 1(PAK1)belongs to PAKs family,a group of highly evolutionarily conserved protein family of serine/threonine kinases,which acts as a downstream effector of the small GTPases Cdc42 and Rac1,firstly reported in 1994[1].As a serine/threonine kinase,PAK1 plays an important role in many cellular functions including cell morphogenesis,motility,survival,mitosis,angiogenesis,     

p21活化激酶4在乳腺癌细胞中的表达及定位

目的:研究p21激活激酶4（PAK4）在人乳腺癌细胞和组织中的表达和定位。方法:蛋白印迹法检测PAK4在人乳腺癌细胞系中蛋白和基因的表达,激光共聚焦扫描显微镜检测内源PAK4在MCF-7乳腺癌细胞中的定位。结果:PAK4在人乳腺肿瘤细胞系中蛋白和基因表达水平增高,激光共聚焦扫描显微镜观察发现PAK4主要定位于MCF-7细胞质中。结论:PAK4在人乳腺癌细胞系中高表达,主要定位于乳腺癌组织细胞质内,可能是人乳腺癌重要的调节因子。     

p21-activated kinases in cancer

The pivotal role of kinases in signal transduction and cellular regulation has lent them considerable appeal as pharmacological targets across a broad spectrum of cancers. p21-activated kinases (Paks) are serine/threonine kinases that function as downstream nodes for various oncogenic signalling pathways. Paks are well-known regulators of cytoskeletal remodelling and cell motility, but have recently also been shown to promote cell proliferation, regulate apoptosis and accelerate mitotic abnormalities, which results in tumour formation and cell invasiveness. Alterations in Pak expression have been detected in human tumours, which makes them an attractive new therapeutic target.     

p21活化激酶1在胰腺癌中的表达及其意义

 目的　探讨p21活化激酶1（PAK1）蛋白在胰腺癌中的表达及其意义。方法　选取胰腺癌组织标本33例作为研究组,胰腺癌周围正常组织标本33例作为对照组,应用免疫组织化学技术检测组织中PAK1蛋白的表达情况。结果　研究组中PAK1蛋白的阳性表达率明显高于对照组[69.7 %（23／33）比27.3 % （9／33）,χ2＝11.89,P＝0.001];且Ⅲ+Ⅳ期胰腺癌组织中PAK1阳性表达率高于Ⅰ+Ⅱ期[93.3 %（14／15）比50.0 %（9／18）, χ2＝5.367,P＝0.021]。结论　PAK1蛋白可能与胰腺癌发生、发展有关。     

p21-activated kinase 1: PAK'ed with potential

The p21-activated kinases (PAKs) are central players in growth factor signaling networks and morphogenetic processes that control proliferation, cell polarity, invasion and actin cytoskeleton organization. This raises the possibility that interfering with PAK activity may produce significant anti-tumor activity. In this perspective, we summarize recent data concerning the contribution of the PAK family member, PAK1, in growth factor signaling and tumorigenesis. We further discuss mechanisms by which inhibition of PAK1 can arrest tumor growth and promote cell apoptosis, and the types of cancers in which PAK1 inhibition may hold promise.     

P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer

BackgroundTherapeutic resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) is attributed to various cellular mechanisms and signaling molecules that influence as a single factor or in combination.DesignIn this study, utilizing in vitro p21-activated kinase 1 (Pak1) overexpression and knockdown cell line models along with in vivo athymic mouse tumor xenograft models and clinical samples, we demonstrate that Pak1 is a crucial signaling kinase in gemcitabine resistance.ResultsPak1 kindles resistance via modulation of epithelial–mesenchymal transition and activation of pancreatic stellate cells. Our results from gemcitabine-resistant and -sensitive cell line models showed that elevated Pak1 kinase activity is required to confer gemcitabine resistance. This was substantiated by elevated levels of phosphorylated Pak1 and ribonucleotide reductase M1 levels in the majority of human PDAC tumors when compared with normal. Delineation of the signaling pathway revealed that Pak1 confers resistance to gemcitabine by preventing DNA damage, inhibiting apoptosis and regulating survival signals via NF-κB. Furthermore, we found that Pak1 is an upstream interacting substrate of transforming growth factor β-activated kinase 1—a molecule implicated in gemcitabine resistance. Molecular mechanistic studies revealed that gemcitabine docks with the active site of Pak1; furthermore, gemcitabine treatment induces Pak1 kinase activity both in vivo and in cell-free system. Finally, results from athymic mouse tumor models illustrated that Pak1 inhibition by IPA-3 enhances the cytotoxicity of gemcitabine and brings about pancreatic tumor regression.ConclusionTo our knowledge, this is the first study illustrating the mechanistic role of Pak1 in causing gemcitabine resistance via multiple signaling crosstalks, and hence Pak1-specific inhibitors will prove to be a better adjuvant with existing chemotherapy modality for PDAC.     

Active p21-activated kinase 1 rescues MCF10A breast epithelial cells from undergoing anoikis

The protein kinase, PAK1, is overexpressed in human breast cancer and may contribute to malignancy through induction of proliferation and invasiveness. In this study, we examined the role of PAK1 in the survival of detached MCF10A breast epithelial cells to test whether it may also regulate the early stages of neoplasia. MCF10A cells undergo anoikis, as measured by the cleavage of caspase 3 and poly(ADP-ribose) polymerase (PARP), after more than 8 hours of detachment. Endogenous Akt, PAK1, and BAD are phosphorylated in attached MCF10A cells, but these phosphorylation events are all lost during the first 8 hours of detachment. Expression of constitutively active PAK1 or Akt suppresses the cleavage of caspase 3 and PARP in detached MCF10A cells. Co-overexpression of active PAK1 with dominant-negative Akt, or of active Akt with dominant-negative PAK1, still suppresses anoikis. Thus, Akt and PAK1 enhance survival through pathways that are at least partially independent. PAK1-dependent regulation of anoikis is likely to occur early in the apoptotic cascade as expression of dominant-negative PAK1 increased the cleavage of the upstream caspase 9, while constitutively active PAK1 inhibited caspase 9 activation. These results support a role for activated PAK1 in the suppression of anoikis in MCF10A epithelial cells.     

p21-activated kinase 5 inhibits camptothecin-induced apoptosis in colorectal carcinoma cells

p21-activated kinase 5 (PAK5) is a recently identified member of the group B PAK family. The PAK proteins are effectors of the small GTPase Cdc42 and Rac1 and are known to regulate cell motility and activate cell-survival signaling pathways. Especially, the mitochondrial localization of PAK5 is vital to its effects on apoptosis and cell survival. Previously, we demonstrated that PAK5 expression increased significantly during the malignant progression of colorectal carcinoma (CRC) and that PAK5 promoted CRC metastasis by regulating CRC cell adhesion and migration. In the present study, we aim to investigate the role of PAK5 in camptothecin-induced apoptosis and its potential mechanism of action. Our results showed that overexpression of PAK5 inhibited camptothecin-induced apoptosis by inhibiting the activity of caspase-8 in CRC cells. Accordingly, knockdown of PAK5 in LoVo cells resulted in increased apoptosis. Mechanistically, we found that PAK5 directly phosphorylated Bad on serine 112 and indirectly led to phosphorylation of serine 136 via the Akt pathway. In conclusion, our study revealed previously unappreciated inhibitory role of PAK5 in camptothecin-induced apoptosis, thus suggesting PAK5 as a novel therapeutic target in CRC.     

p21-激活激酶1在大肠癌组织中的表达及其临床意义

 目的　探讨p21-激活激酶1（PAK1）基因在大肠癌组织中的表达及其临床病理学意义。方法　采用免疫组织化学SABC法检测50例大肠癌组织及癌旁正常组织PAK1基因的表达,并分析其与各临床病理参数之间的关系。结果　癌组织中PAK1蛋白表达阳性率显著高于癌旁正常组织（58 %∶22 %）,差异有统计学意义（P＜0.01）,定位于癌细胞胞质,并与淋巴结转移、组织分化程度密切相关（χ2＝8.872,P＝0.003;χ2＝6.344,P＝0.042）,与肿瘤部位、大小、患者的性别和年龄无关（P＞0.05）。结论　PAK1过度表达同大肠癌的生物学行为密切相关,在大肠癌的发生、发展过程中具有重要的作用。     

PAK Group I的活性减弱促进肺癌细胞对EGFR-TKIs的敏感性

目的:探讨p21活化激酶(p21-activated kinase,PAK)是否影响肺癌细胞对EGFR-TKIs的敏感性.方法:肺癌细胞系中加入PAK Group I抑制剂(IPA3)后,应用MTT、流式细胞术观察肺癌细胞的增殖能力.结果:IPA3和吉非替尼虽然能在不同程度上抑制肺癌细胞的增殖,但二者的联合用药能明显增强对肺癌细胞增殖的抑制作用.结论:PAK Group I的活性减弱后能抑制肺癌细胞的增殖,促进肺癌细胞对EGFR-TKIs的敏感性.     

p21激活激酶在肿瘤中的作用及其靶向治疗

p21激活激酶(p21-activated kinases,Paks)是一类丝氨酸/苏氨酸激酶,在进化上高度保守.Paks可被多种上游信号特别是小G蛋白Rho家族的Rac和Cdc42激活,对多种重要的信号通路及细胞功能进行调控.Paks在多种肿瘤中异常表达,参与细胞骨架重构、细胞运动、细胞增殖、分化、凋亡、有丝分裂及血管生成等,在肿瘤的发生、发展中起重要作用.因此,开展Paks靶向治疗的研究,可为肿瘤治疗提供新的思路.     

P21-activated protein kinase 1 is overexpressed in gastric cancer and induces cancer metastasis

P21-activated protein kinase (Pak1), a main downstream effector of small Rho GTPases, plays an important role in the regulation of cell morphogenesis, motility, mitosis and angiogenesis. However, the role of Pak1 in gastric cancer metastasis remains unclear. Here, we showed that Pak1 is overexpressed in gastric cancer tissues from 74 patients by immunohistochemistry. Overexpression of Pak1 was associated with metastasis and prognosis of gastric cancer. In addition, overexpression of Pak1 increased gastric cancer cell motility and invasion, whereas downregulation of Pak1 expression reduced gastric cancer cell migration and invasion. In further study, data showed that activated Pak1 inhibited stress fiber and focal adhesion complex formation in gastric cancer cells and led to the formation of motile phenotypes. Importantly, activated Pak1 elicited phosphorylation of the ERK and JNK-dependent pathway in gastric cancer cell lines. In conclusion, our results suggest that Pak1 is overexpressed in gastric cancer and plays an important role in the metastasis of gastric cancer. The mechanism by which Pak1 induces cancer metastasis may involve activation of ERK and JNK.     

Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor

Functional versatility and elevated expression in cancers have endowed p21-activated kinase 4 (PAK4) as one of the first-in-class anti-cancer drug target. In this study, a novel PAK4 inhibitor, KY-04031 (N²-(2-(1H-indol-3-yl)ethyl)-N⁴-(1H-indazol-5-yl)-6-methoxy-1,3,5-triazine-2,4-diamine), was discovered using a high-throughput screening. Analysis of the complex crystal structure illustrated that both indole and indazole of KY-04031 are responsible for PAK4 hinge interaction. Moreover, the molecule’s triazine core was found to mimic the ribose of the natural ATP substrate. The cell-based anti-cancer potency of KY-04031 was less effective than the pyrroloaminopyrazoles; however, the unique molecular feature of KY-04031 can be exploited in designing new PAK4 inhibitors.     

Modulation of p21-activated kinase 1 alters the behavior of renal cell carcinoma

The p21-activated kinase 1 (Pak1) is a serine/threonine kinase whose activity is regulated by both Rho GTPases and AGC kinase family members. It plays a role in cytoskeletal remodeling and cell motility as well as cell proliferation, angiogenesis, tumorigenesis and metastasis. An involvement of Pak1 in renal cell carcinoma (RCC), which remains highly refractory to chemotherapy and radiotherapy, remains to be investigated. Pak1 expression, phosphorylation and kinase activity were examined in RCC cell lines and human tissue from normal and renal carcinoma. We report increased Pak1 expression and constitutive activity in the membrane and nucleus but not the cytoplasm of resected human RCC. To study a role for Pak1 in RCC, we developed 786-0 clones that expressed either a kinase-active Pak1L83,L86 2 different Pak1 dominant negative mutants, Pak1R299 and Pak1L83,L86,R299 or Pak1 siRNA. The expression of Pak1L83,L86 increased 786-0 proliferation, motility and anchorage independent growth, while the dominant negative mutants and Pak1 siRNA abrogated these effects. In addition, Pak1L83,L86 conferred resistance to 5-fluorouracil with a 40%+/-10% increase in cell viability. Conversely, Pak1L83,L86,R299, Pak1R299 and Pak1 siRNA conferred sensitivity with a 65.2%+/-5.5%, 69.2%+/-3.3% and 73.0%+/-8.4% loss in viability, respectively. Finally, Pak1 plays a role in renal tumor growth in vivo. Only 33% of mice developed tumors in the Pak1L83,L86,R299 group and no tumors developed from Pak1R299 cell challenge. Together these findings point to Pak1 as an exciting target for therapy of renal cancer, which remains highly refractory to existing treatments.