Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early ...Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemotherapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases(PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemoresistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.展开更多
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
The p21-activated kinase 4(PAK4),a key regulator of malignancy,is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy.Given the lack of high efficacy PAK4 inhibitors...The p21-activated kinase 4(PAK4),a key regulator of malignancy,is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy.Given the lack of high efficacy PAK4 inhibitors,we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC_(50) values of 0.38 and 0.50 mmol/L,respectively.This compound directly binds to PAK4 in a non-ATP competitive manner.In the mouse Pan02 model,compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg,accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue.Overall,compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo,thus making it worthy of further exploration.展开更多
Background Peg-lnterferon-a treatment is expensive and associated with considerable adverse effects, selection of patients with the highest probability of response is essential for clinical practice. The objective of ...Background Peg-lnterferon-a treatment is expensive and associated with considerable adverse effects, selection of patients with the highest probability of response is essential for clinical practice. The objective of this study was to assess the relationship between the gene polymorphisms of interleukin-28 （IL-28）, p21-activated protein kinase 4 （PAK4） and the response to interferon treatment in chronic hepatitis B patients. Methods Two hundred and forty interferon-naive treatment HBeAg seropositive chronic hepatitis B patients were enrolled in the present prospective nested case-control study. Peripheral blood samples were collected, including 92 with favorable response and 148 without response to the interferon treatment. Rs8099917, rs12980602, and rs9676717 SNP was genotyped using matrix assisted laser desorption/ionization time of flight mass spectrometry （MALDI-TOF MS）. Results IL-28 genotype was not associated with response to interferon treatment （OR for GT/GG vs. TT, 0.881 （95% CI 0.388-2.002）; P=0.762; OR for CT/CC vs. TT, 0.902 （95% CI 0.458-1.778）; P=-0.766）. Rs9676717 in PAK4 genotype was independently associated with the response （OR for CT/CC vs. TT, 0.524 （95% CI 0.310-0.888）; P=0.016）. When adjusting for age, gender, smoking, drinking, levels of hepatitis B virus DNA, and alanine aminotransferase （ALT）, rs9676717 genotype TT appeared to be associated with a higher probability of response for interferon treatment （OR, 0.155 （95% CI 0.034-0.700）; P=0.015）. Conclusion Genotype TTfor rs9676717 in PAK4 gene and no drinking may be predictive of the interferon-a treatment success.展开更多
The serine/threonine p21-activated kinases(PAKs),as main effectors of the Rho GTPases Cdc42 and Rac,represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity....The serine/threonine p21-activated kinases(PAKs),as main effectors of the Rho GTPases Cdc42 and Rac,represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity.PAKs show wide expression in the brain,but they differ in specific cell types,brain regions,and developmental stages.PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines.PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders.Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment,comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases,which may also represent potential therapeutic targets of these diseases.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
探讨miRNA-21-3p在急性髓系白血病(AML)患者外周血单个核细胞(PBMC)中的表达水平变化,并分析其临床意义。方法:采用qRT-PCR法测定正常对照和AML患者PBMC的miRNA-21-3p表达水平,根据ROC曲线计算miRNA-21-3p临界值(cut-off值)。体外CCK8...探讨miRNA-21-3p在急性髓系白血病(AML)患者外周血单个核细胞(PBMC)中的表达水平变化,并分析其临床意义。方法:采用qRT-PCR法测定正常对照和AML患者PBMC的miRNA-21-3p表达水平,根据ROC曲线计算miRNA-21-3p临界值(cut-off值)。体外CCK8细胞计数法测定白血病细胞的增殖水平。分别比较不同患者组的miRNA-21-3p表达水平,并根据cut-off值分为大于和小于两组,同时分析其临床预后意义。结果:①急性髓系白血病(AML)患者与正常对照组比较,PBMCmiRNA-21-3p平均表达水平高于正常对照组,其临界cut-of值为1.426^(2^-△△Ct)。②不同组白血病患者miRNA-21-3p水平的比较:未复发组AML患者的PBMC O miRNA-21-3p水平明显低于复发组(P=0.0027),完全缓解(CR)组与未缓解(NR)组的PBMCmiR-21-3p水平差别不明显(t=1.254,P=0.2146),MRD(+)组PBMCmiRNA-21-3p水平高于MRD(-)组(P=0.0001)。③大于和小于临界值两组的临床意义分析:PBMCmiRNA-21-3p小于临界值组的无病生存期(DFS)与大于临界值组无明显差异(P=0.2331),大于临界值组的复发率和微小残留病(MRD)阳性率均高于小于临界值组(P<0.0001)。大于临界值组和低于临界值组相比较,完全缓解率无明显差异,但是PBMCmiRNA-21-3p大于临界值组的5年生存率低于小于临界值组(P=0.0109)。④CCK8细胞计数法测定miRNA-21-3pmimics对白血病细胞增殖的影响。结果表明miR-21-3pmimics对U937、THP1和K562细胞的增殖水平并没有明显的直接作用(P>0.05)。结论:PBMCmiRNA-21-3p水平与白血病预后有关,并以大于和小于临界值分组更为敏感。miRNA-21-3p mimics对U937、THP1和K562细胞的增殖水平没有明显的直接作用。展开更多
基金Pancare Foundation (https://www.pancare.org.au) for supporting the pancreatic cancer research program in the Department of Surgery, University of Melbournesupported by Melbourne International Fee Remission Scholarship (MIFRS)+1 种基金Melbourne International Research Scholarship (MIRS)the Moshe Sambor Scholarship (Pancare Foundation)
文摘Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemotherapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases(PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemoresistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.
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support from the China National Innovation of Science and Technology-2030(Program of Brain Science and Brain-Inspired Intelligence Technology,2021ZD0204004)the National Natural Science Foundation of China(Grants Nos.82273767,82073073,82122045,and 82273948)+3 种基金the Major Projects for Shanghai Zhang jiang National Independent Innovation of China(ZJ2021-ZD-007)Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20210802,China)the Project of Shanghai Institute of Materia Medica,CAS(SIMM0120231001,China)the High-level Innovative Research Institute,Department of Science and Technology of Guangdong Province(2021B0909050003,China).
文摘The p21-activated kinase 4(PAK4),a key regulator of malignancy,is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy.Given the lack of high efficacy PAK4 inhibitors,we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC_(50) values of 0.38 and 0.50 mmol/L,respectively.This compound directly binds to PAK4 in a non-ATP competitive manner.In the mouse Pan02 model,compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg,accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue.Overall,compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo,thus making it worthy of further exploration.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 30972516）, and the Health Department of Hebei Province （No. 20110086 and 20090004）.
文摘Background Peg-lnterferon-a treatment is expensive and associated with considerable adverse effects, selection of patients with the highest probability of response is essential for clinical practice. The objective of this study was to assess the relationship between the gene polymorphisms of interleukin-28 （IL-28）, p21-activated protein kinase 4 （PAK4） and the response to interferon treatment in chronic hepatitis B patients. Methods Two hundred and forty interferon-naive treatment HBeAg seropositive chronic hepatitis B patients were enrolled in the present prospective nested case-control study. Peripheral blood samples were collected, including 92 with favorable response and 148 without response to the interferon treatment. Rs8099917, rs12980602, and rs9676717 SNP was genotyped using matrix assisted laser desorption/ionization time of flight mass spectrometry （MALDI-TOF MS）. Results IL-28 genotype was not associated with response to interferon treatment （OR for GT/GG vs. TT, 0.881 （95% CI 0.388-2.002）; P=0.762; OR for CT/CC vs. TT, 0.902 （95% CI 0.458-1.778）; P=-0.766）. Rs9676717 in PAK4 genotype was independently associated with the response （OR for CT/CC vs. TT, 0.524 （95% CI 0.310-0.888）; P=0.016）. When adjusting for age, gender, smoking, drinking, levels of hepatitis B virus DNA, and alanine aminotransferase （ALT）, rs9676717 genotype TT appeared to be associated with a higher probability of response for interferon treatment （OR, 0.155 （95% CI 0.034-0.700）; P=0.015）. Conclusion Genotype TTfor rs9676717 in PAK4 gene and no drinking may be predictive of the interferon-a treatment success.
基金This work was supported by the National Natural Science Foundation of China(Nos.32070590 and 31871191)the Guangdong Key Project in the“development of new tools for diagnosis and treatment of Autism”(2018B030335001).
文摘The serine/threonine p21-activated kinases(PAKs),as main effectors of the Rho GTPases Cdc42 and Rac,represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity.PAKs show wide expression in the brain,but they differ in specific cell types,brain regions,and developmental stages.PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines.PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders.Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment,comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases,which may also represent potential therapeutic targets of these diseases.
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.
文摘探讨miRNA-21-3p在急性髓系白血病(AML)患者外周血单个核细胞(PBMC)中的表达水平变化,并分析其临床意义。方法:采用qRT-PCR法测定正常对照和AML患者PBMC的miRNA-21-3p表达水平,根据ROC曲线计算miRNA-21-3p临界值(cut-off值)。体外CCK8细胞计数法测定白血病细胞的增殖水平。分别比较不同患者组的miRNA-21-3p表达水平,并根据cut-off值分为大于和小于两组,同时分析其临床预后意义。结果:①急性髓系白血病(AML)患者与正常对照组比较,PBMCmiRNA-21-3p平均表达水平高于正常对照组,其临界cut-of值为1.426^(2^-△△Ct)。②不同组白血病患者miRNA-21-3p水平的比较:未复发组AML患者的PBMC O miRNA-21-3p水平明显低于复发组(P=0.0027),完全缓解(CR)组与未缓解(NR)组的PBMCmiR-21-3p水平差别不明显(t=1.254,P=0.2146),MRD(+)组PBMCmiRNA-21-3p水平高于MRD(-)组(P=0.0001)。③大于和小于临界值两组的临床意义分析:PBMCmiRNA-21-3p小于临界值组的无病生存期(DFS)与大于临界值组无明显差异(P=0.2331),大于临界值组的复发率和微小残留病(MRD)阳性率均高于小于临界值组(P<0.0001)。大于临界值组和低于临界值组相比较,完全缓解率无明显差异,但是PBMCmiRNA-21-3p大于临界值组的5年生存率低于小于临界值组(P=0.0109)。④CCK8细胞计数法测定miRNA-21-3pmimics对白血病细胞增殖的影响。结果表明miR-21-3pmimics对U937、THP1和K562细胞的增殖水平并没有明显的直接作用(P>0.05)。结论:PBMCmiRNA-21-3p水平与白血病预后有关,并以大于和小于临界值分组更为敏感。miRNA-21-3p mimics对U937、THP1和K562细胞的增殖水平没有明显的直接作用。
