ORCID Profile
0000-0002-3610-8430
Current Organisation
University of Adelaide
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Publisher: Springer Science and Business Media LLC
Date: 08-11-2013
DOI: 10.1186/BCR3574
Publisher: Springer Science and Business Media LLC
Date: 15-02-2010
Abstract: The cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) mediated phosphorylation of glucocorticoid receptor (GR) exerts opposite effects on GR transcriptional activity and affects other posttranslational modifications within this protein. The major phosphorylation site of human GR targeted by MAPK family is the serine 226 and multiple kinase complexes phosphorylate receptor at the serine 211 residue. We hypothesize that GR posttranslational modifications are involved in the determination of the cellular fate in human lymphoblastic leukemia cells. We investigated whether UV signalling through alternative GR phosphorylation determined the cell type specificity of glucocorticoids (GCs) mediated apoptosis. We have identified putative Glucocorticoid Response Elements (GREs) within the promoter regulatory regions of the Bcl-2 family members NOXA and Mcl-1 indicating that they are direct GR transcriptional targets. These genes were differentially regulated in CEM-C7-14, CEM-C1-15 and A549 cells by glucocorticoids and JNK pathway. In addition, our results revealed that the S211 phosphorylation was dominant in CEM-C7-14, whereas the opposite was the case in CEM-C1-15 where prevalence of S226 GR phosphorylation was observed. Furthermore, multiple GR isoforms with cell line specific patterns were identified in CEM-C7-14 cells compared to CEM-C1-15 and A549 cell lines with the same antibodies. GR phosphorylation status kinetics, and site specificity as well as isoform variability differ in CEM-C7-14, CEM-C1-15, and A549 cells. The positive or negative response to GCs induced apoptosis in these cell lines is a consequence of the variable equilibrium of NOXA and Mcl-1 gene expression potentially mediated by alternatively phosphorylated GR, as well as the balance of MAPK/CDK pathways controlling GR phosphorylation pattern. Our results provide molecular base and valuable knowledge for improving the GC based therapies of leukaemia.
Publisher: Spandidos Publications
Date: 2012
Abstract: Chronic inflammation is a critical component in breast cancer progression. Pro-inflammatory mediators along with growth/survival factors within the tumor microenvironment potentiate the expression of pro-inflammatory cytokines (IL-1, IL-6, TNF-α), chemotactic cytokines and their receptors (CXCR4, CXCL12, CXCL8) and angiogenic factors (VEGF) that often overcome the effect of anti-inflammatory molecules (IL-4, IL-10) thus evading the host's antitumor immunity. Detailed knowledge, therefore, of the regulatory mechanisms determining cytokine levels is essential to understand the pathogenesis of breast cancer. HIF-1α and NF-κB transcription factors are important players for the establishment of a pro-inflammatory and potentially oncogenic environment. HIF-1α is the key mediator of the cellular response to oxygen deprivation and induces the expression of genes involved in survival and angiogenesis within solid hypoxic tumors. The expression of these genes is often modulated by the p53 tumor suppressor protein that induces apoptosis or cell cycle arrest in neoplastic cells. Functional crosstalk between HIF-1α and p53 pathways mediated by modulators shared between the two transcription factors such as SRC-1 and SIRT-1 differentially regulate the expression of distinct subsets of their target genes under variable stress conditions. In an attempt to shed light on the complex regulatory mechanisms involved in cancer-related inflammation, we investigated the role of the two common p53 and HIF-1α co-regulators SRC-1 and SIRT-1, in the expression of the highly potent metastatic chemokine receptor CXCR4. Both SRC-1 and SIRT-1 overexpression in DSFX-treated MCF-7 cells reduced CXCR4 cellular levels implying that both co-regulators are crucial factors in the determination of the metastatic potential of breast cancer cells.
Publisher: Spandidos Publications
Date: 17-04-2013
Abstract: Normal cells produce energy either through OXPHOS in the presence of oxygen or glycolysis in its absence. Cancer cells produce energy preferably through glycolysis even in the presence of oxygen, thereby, acquiring survival and proliferative advantages. Oncogenes and tumour suppressors control these metabolic pathways by regulating the expression of their target genes involved in these processes. During hypoxia, HIF-1 favours high glycolytic flux by upregulating glycolytic enzymes. Conversely, p53 inhibits glycolysis and increases OXPHOS expression through TIGAR and SCO2 gene expression, respectively. We hypothesise that the p300/CBP-associated factor (PCAF) as a common co-factor shared between p53 and HIF-1 plays an important role in the regulation of energy production by modulating SCO2 and TIGAR gene expression mediated by these two transcription factors. The possible involvement of HIF-1 in the regulation of SCO2 and TIGAR gene expression was investigated in cells with different p53 status in normoxia- and hypoxia-mimicking conditions. Putative hypoxia response elements (HREs) were identified in the regulatory region of SCO2 and TIGAR gene promoters. Chromatin immunoprecipitation experiments suggested that HIF-1 was recruited to the putative HREs present in the SCO2 and TIGAR promoters in a cell type-dependent manner. Transcriptional assays endorsed the notion that PCAF may be involved in the determination of the SCO2 and TIGAR cellular levels, thereby, regulating cellular energy metabolism, a view supported by assays measuring lactic acid production and oxygen consumption in cells ectopically expressing PCAF. The present study identified HIF-1 as a potential regulator of SCO2 and TIGAR gene expression. Furthermore, evidence to suggest that PCAF is involved in the regulation of cellular energy production pathways in hypoxia-mimicking conditions is presented. This effect of PCAF is exerted by orchestrating differential recruitment of HIF-1α and p53 to the promoter of TIGAR and/or SCO2 genes, thereby, tailoring physiological needs and environmental conditions to SCO2 and TIGAR gene expression.
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0NJ00849D
Publisher: Wiley
Date: 08-07-2021
DOI: 10.1111/JCMM.16748
Abstract: Breast cancer has a erse aetiology characterized by the heterogeneous expression of hormone receptors and signalling molecules, resulting in varied sensitivity to chemotherapy. The adverse side effects of chemotherapy coupled with the development of drug resistance have prompted the exploration of natural products to combat cancer. Lactoferricin B (LfcinB) is a natural peptide derived from bovine lactoferrin that exhibits anticancer properties. LfcinB was evaluated in vitro for its inhibitory effects on cell lines representing different categories of breast cancer and in vivo for its suppressive effects on tumour xenografts in NOD‐SCID mice. The different breast cancer cell lines exhibited varied levels of sensitivity to apoptosis induced by LfcinB in the order of SKBR3 MDA‐MB‐231 MDA‐MB‐468 MCF7, while the normal breast epithelial cells MCF‐10A were not sensitive to LfcinB. The peptide also inhibited the invasion of the MDA‐MB‐231 and MDA‐MB‐468 cell lines. In the mouse xenograft model, intratumoural injections of LfcinB significantly reduced tumour growth rate and tumour size, as depicted by live imaging of the mice using in vivo imaging systems (IVIS). Harvested tumour volume and weight were significantly reduced by LfcinB treatment. LfcinB, therefore, is a promising and safe candidate that can be considered for the treatment of breast cancer.
Publisher: Public Library of Science (PLoS)
Date: 04-09-2013
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.JCONREL.2010.04.011
Abstract: Gene silencing by RNA interference (RNAi) is a promising therapeutic approach for a wide variety of diseases for which the biological cause is known. The main challenge remains the ineffective RNAi delivery inside the cells. Non-viral gene delivery vectors have low immunogenicity compared to viral vectors, but are constrained by their reduced transfection efficiency. Silencing of the bcr-abl gene expression by RNAi confers therapeutic potential in Chronic Myeloid Leukemia (CML), but is limited by the cytotoxicity of the existing delivery methods. Here, we present evidence that the fusion between the cell penetrating peptide (CPP) HIV-Tat (49-57) and the membrane lytic peptide (LK15), Tat-LK15, mediates high transfection efficiency in delivering short hairpin RNA (shRNA) and small interfering RNA (siRNA) targeting the BCR-ABL oncoprotein in K562 CML cells. Our results show that shRNA complexes induce a more stable gene silencing of bcr-abl when compared to silencing mediated by siRNA complexes. In addition, silencing of the BCR-ABL oncoprotein by both shRNA and siRNA delivered by Tat-LK15 is more efficient and longer lasting than that achieved using Lipofectamine and more importantly without considerable cytotoxicity. In these terms Tat-LK15 can be an alternative to DNA/siRNA delivery in difficult-to-transfect leukemic cells.
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.CARRES.2012.04.008
Abstract: Ester prodrugs have the potential to eliminate the gastrotoxicity associated with the carboxylic acid group of indomethacin. 4,6-Bis-O-2'-[1'-(4″-chlorobenzoyl)-5'-methoxy-2'-methyl-1'H-indol-3'-acetyl]-myo-inositol-1,3,5-orthoacetate (2) was synthesised and evaluated as a COX-2 inhibitor. It adopts a conformationally restricted chair with two indomethacin groups in the sterically hindered 1,3-diaxial positions. Acid-induced cleavage of the orthoacetate lock of the prodrug leads to a ring flip of the myo-inositol ring with the two indomethacin groups now in 1,3-diequatorial positions. This increases the susceptibility of hydrolysis of the ester groups to release indomethacin under acidic conditions. The long half-life (152 min) of decomposition of (2) at ~pH 1-2 suggests that it may bypass the stomach with minimal hydrolysis upon oral administration. Indomethacin ester (2) was completely stable at pH 4.0-8.5 over 24h at 37°C and showed comparable activity to indomethacin in a COX-2 assay (pH 8.0).
Publisher: Springer Science and Business Media LLC
Date: 23-06-2008
DOI: 10.1038/ONC.2008.192
Publisher: Hindawi Limited
Date: 2011
DOI: 10.1155/2011/368276
Abstract: Transcription is regulated by acetylation/deacetylation reactions of histone and nonhistone proteins mediated by enzymes called KATs and HDACs, respectively. As a major mechanism of transcriptional regulation, protein acetylation is a key controller of physiological processes such as cell cycle, DNA damage response, metabolism, apoptosis, and autophagy. The deacetylase activity of class III histone deacetylases or sirtuins depends on the presence of NAD + (nicotinamide adenine dinucleotide), and therefore, their function is closely linked to cellular energy consumption. This activity of sirtuins connects the modulation of chromatin dynamics and transcriptional regulation under oxidative stress to cellular lifespan, glucose homeostasis, inflammation, and multiple aging-related diseases including cancer. Here we provide an overview of the recent developments in relation to the erse biological activities associated with sirtuin enzymes and stress responsive transcription factors, DNA damage, and oxidative stress and relate the involvement of sirtuins in the regulation of these processes to oncogenesis. Since the majority of the molecular mechanisms implicated in these pathways have been described for Sirt1, this sirtuin family member is more extensively presented in this paper.
Start Date: 2015
End Date: 2017
Funder: Ministry of Higher Education, Malaysia
View Funded ActivityStart Date: 2014
End Date: 2017
Funder: Ministry of Higher Education, Malaysia
View Funded ActivityStart Date: 2014
End Date: 2017
Funder: Ministry of Higher Education, Malaysia
View Funded Activity