P21-activated kinases(PAKs) are central players in various oncogenic signaling pathways. The six PAK family members are classified into group Ⅰ(PAK1-3) and group Ⅱ(PAK4-6). Focus is currently shifting from group Ⅰ ...P21-activated kinases(PAKs) are central players in various oncogenic signaling pathways. The six PAK family members are classified into group Ⅰ(PAK1-3) and group Ⅱ(PAK4-6). Focus is currently shifting from group Ⅰ PAKs to group Ⅱ PAKs. Group Ⅱ PAKs play important roles in many fundamental cellular processes, some of which have particular significance in the development and progression of cancer. Because of their important functions, group Ⅱ PAKs have become popular potential drug target candidates. However, few group Ⅱ PAKs inhibitors have been reported, and most do not exhibit satisfactory kinase selectivity and "drug-like" properties. Isoform- and kinase-selective PAK inhibitors remain to be developed. This review describes the biological activities of group Ⅱ PAKs, the importance of group Ⅱ PAKs in the development and progression of gastrointestinal cancer, and smallmolecule inhibitors of group Ⅱ PAKs for the treatment of cancer.展开更多
T-cell lymphoblastic lymphoma(T-LBL)is a highly aggressive non-Hodgkin lymphoma with a poor prognosis.P21-activated kinase(PAK)is a component of the gene expression-based classifier that can predict the prognosis of T...T-cell lymphoblastic lymphoma(T-LBL)is a highly aggressive non-Hodgkin lymphoma with a poor prognosis.P21-activated kinase(PAK)is a component of the gene expression-based classifier that can predict the prognosis of T-LBL.However,the role of PAK in T-LBL progression and survival remains poorly understood.Herein,we found that the expression of PAK1 was significantly higher in T-LBL cell lines(Jurkat,SUP-T1,and CCRF-CEM)compared to the human T-lymphoid cell line.Moreover,PAK2 mRNA level of 32 relapsed T-LBL patients was significantly higher than that of 37 cases without relapse(P=.012).T-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression(PAK1,P=.028;PAK2,P=.027;PAK1/2,P=.032).PAK inhibitors,PF3758309(PF)and FRAX597,could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition.Besides,PF could enhance the chemosensitivity to doxorubicin in vitro and in vivo.Mechanistically,through western blotting and RNA sequencing,we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1,NF-κB and cell adhesion signaling pathways in T-LBL cell lines.These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin.Collectively,our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy.展开更多
Epidermal growth factor (EGF) may increase cell motility, an event implicated in cancer cell invasion and metastasis. However, the underlying mechanisms for EGF-induced cell motility remain elusive. In this study, w...Epidermal growth factor (EGF) may increase cell motility, an event implicated in cancer cell invasion and metastasis. However, the underlying mechanisms for EGF-induced cell motility remain elusive. In this study, we found that EGF treatment could activate Ras-related C3 botulinum toxin substrate 1 (Racl), PI3K/Akt and p21- actived kinase (PAK1) along with cell migration. Ectopic expression of PAK1 K299R, a dominant negative PAK1 mutant, could largely abolish EGF-induced cell migration. Blocking PI3K/Akt signalling with LY294002 or Akt siRNA remarkably inhibited both EGF-induced PAK1 activation and cell migration. Furthermore, expression of dominant-negative Racl (T17N) could largely block EGF-induced PI3K/Akt-PAK1 activation and cell migration. Interestingly, EGF could induce a significant production of ROS, and N-acetyl-L-cysteine, a scavenger of ROS which abolished the EGF-induced ROS generation, cell migration, as well as activation of PI3K/Akt and PAK, but not Racl. Our study demonstrated that EGF-induced cell migration involves a cascade of signalling events, including activation of Racl, generation of ROS and subsequent activation of PI3K/Akt and PAK1.展开更多
BACKGROUND Pediatric enteritis is one of the infectious diseases in the digestive system that causes a variety of digestive problems,including diarrhea,vomiting,and bellyache in children.Clinically,Helicobacter pylori...BACKGROUND Pediatric enteritis is one of the infectious diseases in the digestive system that causes a variety of digestive problems,including diarrhea,vomiting,and bellyache in children.Clinically,Helicobacter pylori(H.pylori)infection is one of the common factors to cause pediatric enteritis.It has been demonstrated that aberrant expression of microRNAs(miRNAs)is found in gastrointestinal diseases caused by H.pylori,and we discovered a significant increase of miR-32-5p in H.pylori-related pediatric enteritis.However,the exact role of miR-32-5p in it is still unknown.AIM To investigate the role of aberrant miR-32-5p in pediatric enteritis induced by H.pylori.METHODS MiR-32-5p expression was detected by quantitative real time-polymerase chain reaction.The biological role of miR-32-5p in H.pylori-treated intestinal epithelial cells was evaluated by Cell Counting Kit-8 assay and flow cytometry.The potential target of miR-32-5p was predicted with TargetScanHuman and verified by luciferase assay.The downstream mechanism of miR-32-5p was explored by using molecular biology methods.RESULTS We found that miR-32-5p was overexpressed in serum of H.pylori-induced pediatric enteritis.Further investigation revealed that H.pylori infection promoted the death of intestinal epithelial cells,and increased miR-32-5p expression.Moreover,miR-32-5p mimic further facilitated apoptosis and inflammatory cytokine secretion of intestinal epithelial cells.Further exploration revealed that SMAD family member 6(SMAD6)was the direct target of miR-32-5p,and SMAD6 overexpression partially rescued cell damage induced by H.pylori.The following experiments showed that miR-32-5p/SMAD6 participated in the apoptosis of intestinal epithelial cells induced by transforming growth factor-β-activated kinase 1(TAK1)-p38 activation under H.pylori infection.CONCLUSION Our work uncovered the crucial role of aberrant expression of miR-32-5p in H.pylori–related pediatric enteritis,and suggested that the TAK1-p38 pathway is involved in it.展开更多
We review here the novel cardiac protective effects of the multifunctional enzyme, p21-aetivated kinase 1 (PAK1), a member of a serine/threonine protein kinase family. Despite the large body of evidence from studies...We review here the novel cardiac protective effects of the multifunctional enzyme, p21-aetivated kinase 1 (PAK1), a member of a serine/threonine protein kinase family. Despite the large body of evidence from studies in noncardiac tissue indicating that PAK1 activity is key in the regulation of a number of cellular functions, the role of PAK1 in the heart has only been revealed over the past few years. In this review, we assemble an overview of the recent findings on PAKI signaling in the heart, particularly its cardiac protective effects. We present a model for PAK1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by protein phosphatase 2A (PP2A) predominates. We discuss the anti-adrenergic and antihypertrophic cardiac protective effects of PAK1, as well as its role in maintaining ventricular Ca2+ homeostasis and electrophysiological stability under physiological, β-adrenergic and hypertrophic stress conditions.展开更多
基金Supported by National Natural Science Foundation of ChinaNo.90813038+2 种基金No.31271389No.31371424No.31171360 and No.81230077
文摘P21-activated kinases(PAKs) are central players in various oncogenic signaling pathways. The six PAK family members are classified into group Ⅰ(PAK1-3) and group Ⅱ(PAK4-6). Focus is currently shifting from group Ⅰ PAKs to group Ⅱ PAKs. Group Ⅱ PAKs play important roles in many fundamental cellular processes, some of which have particular significance in the development and progression of cancer. Because of their important functions, group Ⅱ PAKs have become popular potential drug target candidates. However, few group Ⅱ PAKs inhibitors have been reported, and most do not exhibit satisfactory kinase selectivity and "drug-like" properties. Isoform- and kinase-selective PAK inhibitors remain to be developed. This review describes the biological activities of group Ⅱ PAKs, the importance of group Ⅱ PAKs in the development and progression of gastrointestinal cancer, and smallmolecule inhibitors of group Ⅱ PAKs for the treatment of cancer.
基金supported by grants from the National Key Research and Development Program(No.2022YFC2502602 to Dr.Q.C.)the National Natural Science Foundation project(Nos.82230001 and 82270199 to Dr.Q.C.,No.81973384 to Dr.X.T.)the Medical Research Foundation of Guangdong Province(No.A2023488 to Dr.Y.F.).
文摘T-cell lymphoblastic lymphoma(T-LBL)is a highly aggressive non-Hodgkin lymphoma with a poor prognosis.P21-activated kinase(PAK)is a component of the gene expression-based classifier that can predict the prognosis of T-LBL.However,the role of PAK in T-LBL progression and survival remains poorly understood.Herein,we found that the expression of PAK1 was significantly higher in T-LBL cell lines(Jurkat,SUP-T1,and CCRF-CEM)compared to the human T-lymphoid cell line.Moreover,PAK2 mRNA level of 32 relapsed T-LBL patients was significantly higher than that of 37 cases without relapse(P=.012).T-LBL patients with high PAK1 and PAK2 expression had significantly shorter median RFS than those with low PAK1 and PAK2 expression(PAK1,P=.028;PAK2,P=.027;PAK1/2,P=.032).PAK inhibitors,PF3758309(PF)and FRAX597,could suppress the proliferation of T-LBL cells by blocking the G1/S cell cycle phase transition.Besides,PF could enhance the chemosensitivity to doxorubicin in vitro and in vivo.Mechanistically,through western blotting and RNA sequencing,we identified that PF could inhibit the phosphorylation of PAK1/2 and downregulate the expression of cyclin D1,NF-κB and cell adhesion signaling pathways in T-LBL cell lines.These findings suggest that PAK might be associated with T-LBL recurrence and further found that PAK inhibitors could suppress proliferation and enhance chemosensitivity of T-LBL cells treated with doxorubicin.Collectively,our present study underscores the potential therapeutic effect of inhibiting PAK in T-LBL therapy.
基金supported by grants from the National Natural Science Foundation of China (No. 30872926)the Program for AdvancedTalents within Six Industries of Jiangsu Province (08-D) to Dr. Luo Gu+1 种基金the Science Development Foundation of Nanjing Medical University (No. 2010NJMUZ35)the Research Program funded by Schoolof Basic Medical Science, Nanjing Medical University to Dr. Jun Du
文摘Epidermal growth factor (EGF) may increase cell motility, an event implicated in cancer cell invasion and metastasis. However, the underlying mechanisms for EGF-induced cell motility remain elusive. In this study, we found that EGF treatment could activate Ras-related C3 botulinum toxin substrate 1 (Racl), PI3K/Akt and p21- actived kinase (PAK1) along with cell migration. Ectopic expression of PAK1 K299R, a dominant negative PAK1 mutant, could largely abolish EGF-induced cell migration. Blocking PI3K/Akt signalling with LY294002 or Akt siRNA remarkably inhibited both EGF-induced PAK1 activation and cell migration. Furthermore, expression of dominant-negative Racl (T17N) could largely block EGF-induced PI3K/Akt-PAK1 activation and cell migration. Interestingly, EGF could induce a significant production of ROS, and N-acetyl-L-cysteine, a scavenger of ROS which abolished the EGF-induced ROS generation, cell migration, as well as activation of PI3K/Akt and PAK, but not Racl. Our study demonstrated that EGF-induced cell migration involves a cascade of signalling events, including activation of Racl, generation of ROS and subsequent activation of PI3K/Akt and PAK1.
文摘BACKGROUND Pediatric enteritis is one of the infectious diseases in the digestive system that causes a variety of digestive problems,including diarrhea,vomiting,and bellyache in children.Clinically,Helicobacter pylori(H.pylori)infection is one of the common factors to cause pediatric enteritis.It has been demonstrated that aberrant expression of microRNAs(miRNAs)is found in gastrointestinal diseases caused by H.pylori,and we discovered a significant increase of miR-32-5p in H.pylori-related pediatric enteritis.However,the exact role of miR-32-5p in it is still unknown.AIM To investigate the role of aberrant miR-32-5p in pediatric enteritis induced by H.pylori.METHODS MiR-32-5p expression was detected by quantitative real time-polymerase chain reaction.The biological role of miR-32-5p in H.pylori-treated intestinal epithelial cells was evaluated by Cell Counting Kit-8 assay and flow cytometry.The potential target of miR-32-5p was predicted with TargetScanHuman and verified by luciferase assay.The downstream mechanism of miR-32-5p was explored by using molecular biology methods.RESULTS We found that miR-32-5p was overexpressed in serum of H.pylori-induced pediatric enteritis.Further investigation revealed that H.pylori infection promoted the death of intestinal epithelial cells,and increased miR-32-5p expression.Moreover,miR-32-5p mimic further facilitated apoptosis and inflammatory cytokine secretion of intestinal epithelial cells.Further exploration revealed that SMAD family member 6(SMAD6)was the direct target of miR-32-5p,and SMAD6 overexpression partially rescued cell damage induced by H.pylori.The following experiments showed that miR-32-5p/SMAD6 participated in the apoptosis of intestinal epithelial cells induced by transforming growth factor-β-activated kinase 1(TAK1)-p38 activation under H.pylori infection.CONCLUSION Our work uncovered the crucial role of aberrant expression of miR-32-5p in H.pylori–related pediatric enteritis,and suggested that the TAK1-p38 pathway is involved in it.
基金The work was supported by the Medical Research Council (G10002647: ML, XW, EJC, RJS, YBK), the British Heart Foundation (PG/12/21/29473: ML, XW) and the National Natural Science Foundation of China (No. 31171085: ML), NIH Grant HL 064035 (RJS), POI HL 062426 (RJS). The authors thank Dr. Emma Bolton for her proof checking and suggestions for improving the manuscript.
文摘We review here the novel cardiac protective effects of the multifunctional enzyme, p21-aetivated kinase 1 (PAK1), a member of a serine/threonine protein kinase family. Despite the large body of evidence from studies in noncardiac tissue indicating that PAK1 activity is key in the regulation of a number of cellular functions, the role of PAK1 in the heart has only been revealed over the past few years. In this review, we assemble an overview of the recent findings on PAKI signaling in the heart, particularly its cardiac protective effects. We present a model for PAK1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by protein phosphatase 2A (PP2A) predominates. We discuss the anti-adrenergic and antihypertrophic cardiac protective effects of PAK1, as well as its role in maintaining ventricular Ca2+ homeostasis and electrophysiological stability under physiological, β-adrenergic and hypertrophic stress conditions.