ABSTRACT
The p21-activated kinase 1 (PAK1) is a member of the P21-activated protein kinase family that plays an important role in the proliferation and on cogenesis of pancreatic cancer. PAK1 is an important target for the treatment of pancreatic cancer. At present, akinase inhibitor targeting PAK1 is still in the preclinical research stage. Therefore, screening for new PAK1 kinase inhibitors is of great significance. In this study the natural compound celastrol was found to have a significant inhibitory effect on PAK1, with an IC50 value of 3.614 μmol·L-1. Molecular docking results showed that celastrol had good binding to PAK1. An MTT assay indicated that celastrol inhibited the proliferation of pancreatic cancer cells BxPC-3 and PANC-1. Mechanistic studies revealed that the inhibition of pancreatic cancer cells by celastrol was reversed by PAK1 siRNA. Celastrol inhibited PAK1 and the subsequent activation of downstream signaling pathways, thereby activating apoptosis signaling pathways and triggering apoptosis in pancreatic cancer cells. These findings suggested that celastrol induced apoptosis in pancreatic cancer cells by suppressing the PAK1 kinase signaling pathway and has potential value for the treatment of pancreatic cancer.
ABSTRACT
Objective@#To investigate the expressions of migration and invasion inhibitory protein (MIIP) and p21-activated kinase 1 (PAK1) in endometrial carcinoma (EC) and their correlation with clinicopathological features.@*Methods@#The protein levels of MIIP and PAK1 in 135 paraffin-embedded EC tissues, 55 atypical hyperplasia of endometrium (AHE) and 88 normal endometrium (NE) tissues were quantified by immunohistochemistry, the clincial significance and the relationship of these two proteins were also analyzed.@*Results@#The positive rates of MIIP expression in NE, AHE and EC tissues were 52.3%(46/88), 41.8% (23/55) and 34.8% (47/135), respectively. The expression of MIIP in EC was significantly lower than that of MIIP in NE (P<0.05). The positive rates of PAK1 expression in NE, AHE and EC tissues were 45.5% (40/88), 50.9% (28/55) and 62.2% (84/135), respectively. The expression of PAK1 in EC tissues was significantly higher than that of PAK1 in NE tissues (P<0.05). The expression of MIIP in EC tissues was significantly associated with myometrial invasion, International Federation of Gynaecology and Obstetrics (FIGO) stage and lymph node metastasis (P<0.05). The expression of PAK1 in EC tissues was significantly related with differentiation, myometrial invasion, FIGO stage and lymph node metastasis (P<0.05). The expressions of MIIP and PAK1 in EC tissues were marginally related with the overall survival of patients (P=0.092, P=0.052). The expression of MIIP in EC was negatively correlated with PAK1 (r=-0.329, P<0.001).@*Conclusions@#The down-regulation of MIIP and up-regualtion of PAK1 paticipate in the initiation and development of EC, which are correlated with the poor prognosis of EC. The protein expression of MIIP is inversely related with PAK1 in EC.
ABSTRACT
Objective To investigate the effect of p21-activated kinase 1 on chemotherapy sensitivity of 5-fluorouracil. Methods Cell proliferation was measured by CCK8 and apoptosis rate by flow cytometry or Hoechst staining; the expression of Bcl-xl, Bcl-2, XIAP were determined by Western Blot. Results 5-FU combined shRNA-Pak1 group (combination group) could be significantly inhibited in terms of proliferation (P <0.05). The percentage of apoptosis rate in combined group was the highest and the difference among groups indicated statistical significance (P < 0.05). The expression of Bcl-xl, Bcl-2, XIAP in combination group was significantly inhibited compared with 5-FU group or shRNA-Pak1 group. Conclusion PAK1 inhibited by RNA interference can enhance chemotherapy sensitivity of 5-Fu on growth inhibition and apoptosis induction in colon cancer significantly.
ABSTRACT
CardiovascuIar disease is the number one cause for morbidity and mortaIity worIdwide. Possi-biIities for new therapies in the emerging fieId of cardiac signaIIing prompted extensive research on myocardiaI re-modeIIing over the past decades. In this review,we as-sembIe an overview of the recent findings on the muIti-functionaI enzyme,p21-activated kinase 1( Pak1),a member of a serine/ threonine protein kinase famiIy in the heart,particuIarIy its cardiac protective effects. We pres-ent a modeI for Pak1 signaIing that provides a mecha-nism for specificaIIy affecting cardiac ceIIuIar processes. We discuss its cardiac protective effects such as anti-hy-pertrophy,anti-ischaemic injury and roIe in maintaining ventricuIar Ca2+ homeostasis and eIectrophysioIogicaI stabiIity under physioIogicaI, β-adrenergic and hyper-trophic stress conditions.We aIso discuss the potentiaIs of Pak1 activation by naturaIIy occurring sphingosine and its anaIogues FTY720,and bioactive peptides designed to diminish Pak1 auto-inhibition as noveI thera-peutics for major cardiovascuIar diseases.
ABSTRACT
Objective To investigate the effect of ginsenosides-Rb1(Gs-Rb1) on doxorubicin (Dox)-induced heart failure (HF), and the related mechanisms of connexin 43 (CX43) thereof. Methods Rats with Dox-induced HF were ran-domly divided into Dox group (n=15) and Gs-Rb1 group (n=17), and the health age-matched rats were as control (n=15). In addition, cardiomyocytes were randomly divided into Dox group, Gs-Rb1 group and control group. After the intervention, echocardiography or apoptotic ratio (AR) was analyzed, respectively. The expression levels of p21-activated kinase 1 (PAK1), protein phosphatase type 2A (PP2A) and CX43 were detected by Western bolt or RT-PCR analysis, respectively. Re-sults Gs-Rb1 significantly improved heart function in rats with HF, decreased left ventricular mass index and inhibited the cell apoptosis induced by Dox. Both mRNA and protein expressions of CX43 were significantly decreased in Dox group than those of control group. The expression of CX43 was significantly increased in Gs-Rb1 group, which was significantly lower than that of control group. There was no significant difference in PAK1 between Dox group and control group (P>0.05). The expression of PAK1 was significantly up-regulated by Gs-Rb1. The PP2A protein was significantly up-regulated in Dox group than that of control group, which was significantly higher in Gs-Rb1 group than that of Dox group. Conclusion Gs-Rb1 improved HF by adjusting CX43, which may be mediated by PAK1-PP2A.
ABSTRACT
Objective To investigate the role of p21-activated kinase 1 (PAK1) in colorectal mucosal carcinogenesis and the relationship between PAK1 expression and biological behavior of colorectal carcinoma. Method PAK1 was detected with immunohistochemical method in 10 normal colorectal mucosas,40 colorectal villous or tubular adenomas and 60 colorectal carcinomas. Results The positive rate for PAK1 was 10.0% in normal colorectal mucesas,and 25.0%, 33.3% and 33.3% in slight, moderate and severe dys-plastic adenomas, respectively, 65.0% was found in colorectul carcinomas. The positive rate for PAK1 in col-orectal carcinomas was higher than that in normal colorectal mucosas(P<0.01), colorectal villous or tubular adenomas(P<0.01), slight dysplastic adenomas(P<0.01) and moderate dysplastic adenomas (P<0.05).The positive rate for PAK1 of poor differentiated colorectal carcinomas was higher than that of high differentiated ones (P<0.05), and the positive rate for PAK1 of patients with lymph node metastasis was higher than that of patients without lymph node metastasis (P<0.05). In clinical stages, the positive rate for PAK1 in Dukes C and D stages patients was higher than that in Dukes A stage patients, respectively (P<0.05). Conclusion PAK1 maybe play some role in the process of carcinogenesis of colorectal mucesa, and be used as an useful marker for assessment of the biological behavior and prognosis of colorectal carcinoma.