IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-kB activation

Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to the high incidences of metastasis and tumor recurrence. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is frequently observed in HCC and is associated with a more aggressive tumor behavior, suggesting that PAK1 is a potential therapeutic target in HCC. In the current study, an allosteric small molecule PAK1 inhibitor, IPA-3, was evaluated for the potential in suppressing hepatocarcinogenesis. Consistent with other reports, inhibition of PAK1 activity was observed in several human HCC cell lines treated with various dosages of IPA-3. Using cell proliferation, colony formation and BrdU incorporation assays, we demonstrated that IPA-3 treatment significantly inhibited the growth of HCC cells. The mechanisms through which IPA-3 treatment suppresses HCC cell growth are enhancement of apoptosis and blockage of activation of NF-κB. Furthermore, our data suggested that IPA-3 not only inhibits the HCC cell growth, but also suppresses the metastatic potential of HCC cells. Nude mouse xenograft assay demonstrated that IPA-3 treatment significantly reduced the tumor growth rate and decreased tumor volume, indicating that IPA-3 can suppress the in vivo tumor growth of HCC cells. Taken together, our demonstration of the potential preclinical efficacy of IPA-3 in HCC provides the rationale for cancer therapy.published_or_final_versio

PAK4 phosphorylates p53 at serine 215 to promote liver cancer metastasis

PAK4 kinase contributes to signaling pathways controlling cancer cell transformation, invasion and survival, but its clinicopathological impact has begun to emerge only recently. Here we report that PAK4 overexpression in hepatocellular carcinoma (HCC) conveys aggressive metastatic properties. A novel nuclear splice isoform of PAK4 lacking exon 2 sequences was isolated as part of our studies. By stably overexpressing or silencing PAK4 in HCC cells we showed that it was critical for their migration. Mechanistic investigations in this setting revealed that PAK4 directly phosphorylated p53 at S215, which not only attenuated transcriptional transactivation activity but also inhibited p53-mediated suppression of HCC cell invasion. Taken together, our results showed how PAK4 overexpression in HCC promotes metastatic invasion by regulating p53 phosphorylation.postprin

The two PPX-GppA homologues from Mycobacterium tuberculosis have distinct biochemical activities

Inorganic polyphosphate (poly-P), guanosine pentaphosphate (pppGpp) and guanosine tetraphosphate (ppGpp) are ubiquitous in bacteria. These molecules play a variety of important physiological roles associated with stress resistance, persistence, and virulence. In the bacterial pathogen Mycobacterium tuberculosis, the identities of the proteins responsible for the metabolism of polyphosphate and (p)ppGpp remain to be fully established. M. tuberculosis encodes two PPX-GppA homologues, Rv0496 (MTB-PPX1) and Rv1026, which share significant sequence similarity with bacterial exopolyphosphatase (PPX) and guanosine pentaphosphate 5′-phosphohydrolase (GPP) proteins. Here we delineate the respective biochemical activities of the Rv0496 and Rv1026 proteins and benchmark these against the activities of the PPX and GPP proteins from Escherichia coli. We demonstrate that Rv0496 functions as an exopolyphosphatase, showing a distinct preference for relatively short-chain poly-P substrates. In contrast, Rv1026 has no detectable exopolyphosphatase activities. Analogous to the E. coli PPX and GPP enzymes, the exopolyphosphatase activities of Rv0496 are inhibited by pppGpp and, to a lesser extent, by ppGpp alarmones, which are produced during the bacterial stringent response. However, neither Rv0496 nor Rv1026 have the ability to hydrolyze pppGpp to ppGpp; a reaction catalyzed by E. coli PPX and GPP. Both the Rv0496 and Rv1026 proteins have modest ATPase and to a lesser extent ADPase activities. pppGpp alarmones inhibit the ATPase activities of Rv1026 and, to a lesser extent, the ATPase activities of Rv0496. We conclude that PPX-GppA family proteins may not possess all the catalytic activities implied by their name and may play distinct biochemical roles involved in polyphosphate and (p)ppGpp metabolic pathways. © 2012 2012 Choi et al.published_or_final_versio

Clinical significance of frizzled homolog 3 protein in colorectal cancer patients

2013-2014 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

A comparative study of sagittal correction with the Herbst appliance in two different ethnic groups

The dentofacial morphology of Chinese is different from Caucasians. The purpose of this investigation was to assess the skeletal and dental changes contributing to the sagittal correction in a group of consecutive Chinese children who were treated with the Herbst appliance. A comparison was made between 14 Chinese and 14 Swedish subjects who all had Herbst appliance treatment. All subjects were corrected from the Class II division 1 malocclusion to an overcorrected Class I or Class III dental relationship within a 6-8 month period. Lateral cephalograms taken before and immediately after the Herbst treatment were analysed. In general, the skeletal and dental changes during treatment were comparable between both ethnic groups. However, individual variations within the two groups were wide. It can be concluded that the Herbst appliance was equally successful in Southern Chinese children and similar treatment changes as those achieved in Swedish children could be found.link_to_OA_fulltex

Associations between sport participation and knee symptoms : a cross-sectional study involving 3053 undergraduate students

202006 bcrcVersion of RecordSelf-fundedPublishe

Characterization and mutational analysis of an exopolyphosphatase from Mycobacterium smegmatis

Oral Communication Session 6: abstract no. 134Inorganic polyphosphate (poly-P) is a linear polymer comprising tens to hundreds of orthophosphate residues linked by ‘high-energy' phosphoanhydride bonds. These bio-polymers are found within all living cells, and have been shown to have a wide variety of important physiological functions. In most bacteria, the hydrolysis of Poly-P chains to monophosphate is predominantly mediated by exopolyphosphatase (Ppx) enzymes. However many bacterial species, lack identifiable Ppx enzymes. Mycobacterium smegmatis, an important model organism for tuberculosis-related experimental systems, lacks an identifiable Ppx protein, but encodes a protein sharing homology with both guanosine pentaphosphate hydrolase and Ppx enzymes (Msmeg_5413) ...link_to_OA_fulltextThe 25th IADR-SEA Division Annual Scientific Meeting, Singapore, 28-30 October 2011

Ultrasonographic measurement of subarachnoid space in normal infants and children

This study was undertaken to evaluate the sonographic measurement of subarachnoid spaces in normal children and its relationship with age and to define a normal range in a Chinese population and to differentiate normal variant findings from pathologic dilatation. The subarachnoid spaces in 278 normal term neonates, infants, and children were studied with real-time ultrasound using a 7.5-MHz vector transducer. The craniocortical width, sinocortical width, and interhemispheric width were measured in the coronal plane at the level of the foramen of Monro, on either side of the hemispheres. Correlation of sonographic measurements with age was made. The mean widths were plotted against age. A correlation with age was found in all three spaces, with an increasing trend with age until 28 weeks of gestation. Thereafter, a decreasing trend was noted. The normal upper limit of subarachnoid spaces for children is proposed to be the values on the ninety-fifth percentile of the regression curve. Correlation of measurement with age must be considered to decide whether an increase in subarachnoid space is pathologic or not. © 2001 Elsevier Science Inc. All rights reserved.link_to_subscribed_fulltex

Predictive factors for developing musculoskeletal disorders among healthcare students : a systematic review

202304 bcwhOther VersionSelf-funde

An investigation on p21-activated protein kinase 1 inhibitor, IPA-3, in hepatocellular carcinoma

Poster Session 20 - Pathogenesis of Gastrointestinal and Hepatocellular Carcinomas: abstract no. 4429BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide and is associated with poor prognosis due to metastasis and tumor recurrence. However, apart from Sorafenib, there is no proven effective systemic chemotherapy for HCC yet. Our previous study showed that overexpression of p21-activated protein kinase 1 (PAK1) is commonly found in HCC, which is coupled with a more aggressive tumor behavior. In this study, we examined the effect of an allosteric inhibitor of PAK1, IPA-3, on hepatocarcinogenesis. METHODS: Human HCC line H2M was treated with various dosages of IPA-3 or ...link_to_OA_fulltextThe 103rd Annual Meeting of the American Association for Cancer Research (AACR 2012), Chicago, IL., 31 March-4 April 2012