Group Ⅱ p21-activated kinases as therapeutic targets in gastrointestinal cancer

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.

Targeting P21-activated kinase suppresses proliferation and enhances chemosensitivity in T-cell lymphoblastic lymphoma

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.

Molecular determinants of the antitumor effects of trichostatin A in pancreatic cancer cells

AIM:To gain molecular insights into the action of the histone deacetylase inhibitor(HDACI) trichostatin-A(TSA) in pancreatic cancer(PC) cells.METHODS:Three PC cell lines,BxPC-3,AsPC-1 and CAPAN-1,were treated with various concentrations of TSA for def ined periods of time.DNA synthesis was assessed by measuring the incorporation of 5-bromo-2'deoxyuridine.Gene expression at the level of mRNA was quantif ied by real-time polymerase chain reaction.Expression and phosphorylation of proteins was monitored by immunoblotting,applying an infrared imaging technology.To study the role of p38 MAP kinase,the specif ic enzyme inhibitor SB202190 and an inactive control substance,SB202474,were employed.RESULTS:TSA most eff iciently inhibited BrdU incorporation in BxPC-3 cells,while CAPAN-1 cells displayed the lowest and AsPC-1 cells an intermediate sensitivity.The biological response of the cell lines correlated with the increase of histone H3 acetylation after TSA application.In BxPC-3 cells(which are wild-type for KRAS),TSA strongly inhibited phosphorylation of ERK 1/2 and AKT.In contrast,activities of ERK and AKT in AsPC-1 and CAPAN-1 cells(both expressing oncogenic KRAS) were not or were only modestly affected by TSA treatment.In all three cell lines,but most pronounced in BxPC-3 cells,TSA exposure induced an activation of the MAP kinase p38.Inhibition of p38 by SB202190 slightly but signif icantly diminished the antiproliferative effect of TSA in BxPC-3 cells.Interestingly,only BxPC-3 cells responded to TSA treatment by a signif icant increase of the mRNA levels of bax,a pro-apoptotic member of the BCL gene family.Finally,in BxPC-3 and AsPC-1 cells,but not in the cell line CAPAN-1,signif icantly higher levels of the cell cycle inhibitor protein p21Waf1 were observed after TSA application.CONCLUSION:The biological effect of TSA in PC cells correlates with the increase of acetyl-H3,p21Waf1,phospho-p38 and bax levels,and the decrease of phosphoERK 1/2 and phospho-AKT.

Effect of Yanggan Jiedu Sanjie formula on human hepatocellular carcinoma Bel-7402 cells

OBJECTIVE: To observe the effect of Yanggan Jiedu Sanjie(YGJDSJ) formula on human hepatocellular carcinoma Bel-7402 cells.METHODS: Bel-7402 cells were treated with YGJDSJ. Cell proliferation was detected by cell counting kit-8 assay. Cell apoptosis was identified by Hoechst 33258 staining and flow cytometric analysis. Cell cycle distribution was quantified by flow cytometric analysis. Caspase activities were measured by commercial kit. Cell senescence was detected by senescence-associated β-galactosidase(SA-β-gal)staining. Protein expression and phosphorylation were identified by Western blot. Protein expression was knocked-down by siRNA.RESULTS: YGJDSJ inhibited proliferation of Bel-7402 cells in a dose-and time-dependent manner.YGJDSJ induced apoptosis and activated caspase-3, 8, and 9 in Bel-7402 cells. YGJDSJ-induced apoptosis was completely abrogated by a pan caspase inhibitor, Z-VAD-FMK. YGJDSJ also induced cell senescence, up-regulated cyclin-dependent kinase inhibitor 1 a(CDKN1 a) and CDKN2 a expression and down-regulated retinoblastoma protein(RB) phosphorylation in Bel-7402 cells. Specific knockdown of CDKN1 a and CDKN2 a significantly reduced YGJDSJ-induce cell senescence in Bel-7402 cells.CONCLUSION: YGJDSJ inhibited cell proliferation,induced caspase-dependent apoptosis and CDKN1 a/CDKN2 a-RB signalling mediated cell senescence in Bel-7402 cells. Our findings suggest that YGJDSJ might be potential for hepatocellular carcinoma treatment.

Jab1与头颈肿瘤

p27Kip1是一种细胞周期抑制剂,其低表达与肿瘤的不良预后密切相关,被认为是一种抑癌基因.而c-Jun活化区结合蛋白1(c-jun-activation-domain binding protein,Jab1)是新近发现的一种多功能蛋白,其在头颈肿瘤中的表达有助于了解肿瘤的发生、发展和预后,对肿瘤的治疗提供生物学依据.本文就Jab1与头颈肿瘤的关系做一综述.