Graham S Baldwin

University of Melbourne, Melbourne, Victoria, Australia

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Publications (190)856.58 Total impact

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    35th Congress of the Société Internationale d'Urologie, Melbourne, Australia; 10/2015
  • Kathryn M Marshall · Marie Laval · Ioulia Sims · Arthur Shulkes · Graham S Baldwin ·
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    ABSTRACT: Non-amidated gastrin peptides such as glycine-extended gastrin (Ggly) are biologically active in vitro and in vivo and have been implicated in the development of gastric and colonic cancers. Previous studies have shown that the truncated form of Ggly, the octapeptide LE5AY, was still biologically active in vitro, and that activity was dependent on ferric ion binding but independent of binding to the cholecystokinin 2 (CCK2) receptor. The present work was aimed at creating more stable gastrin-derived 'super agonists' using retro-inverso technology. The truncated LE5AY peptide was synthesized using end protecting groups in three forms with L-amino acids (GL), D-amino acids (GD) or retro-inverso (reverse order with D-amino acids; GRI). All of these peptides bound ferric ions with a 2:1 (Fe: peptide) ratio. As predicted, Ggly, GL and GRI were biologically active in vitro and increased cell proliferation in mouse gastric epithelial (IMGE-5) and human colorectal cancer (DLD-1) cell lines, and increased cell migration in DLD-1 cells. These activities were likely via the same mechanism as Ggly since no CCK1 or CCK2 binding was identified, and GD remained inactive in all assays. Surprisingly, unlike Ggly, GL and GRI were not active in vivo. While Ggly stimulated colonic crypt height and proliferation rates in gastrin knockout mice, GL and GRI did not. The apparent lack of activity may be due to rapid clearance of these smaller peptides. Nevertheless further work designing and testing retro-inverso gastrins is warranted, as it may lead to the generation of super agonists that could potentially be used to treat patients with gastrointestinal disorders with reduced mucosal function.
    Peptides 10/2015; 74. DOI:10.1016/j.peptides.2015.09.012 · 2.62 Impact Factor
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    ABSTRACT: Over-expression of growth factors can contribute to the development and progression of cancer, and gastrins in particular have been implicated in accelerating the development of gastrointestinal cancers. Previously our group showed that hypoxia, cobalt chloride (a hypoxia mimetic) and zinc chloride could activate the expression of the gastrin gene in vitro. To characterise activation of the gastrin promoter by zinc ions further in vivo, TALEN technology was used to engineer a luciferase reporter construct into the endogenous human gastrin gene promoter in SW480 colon cancer cells. Gastrin promoter activity in the resultant Gast(luc) SW480 colon cancer cells was then measured by bioluminescence in cell culture and in tumour xenografts in SCID mice. Activation of intracellular signalling pathways was assessed by Western blotting. Activation of the gastrin promoter by zinc ions was concentration dependent in vitro and in vivo. Zinc ions significantly stimulated phosphorylation of ERK1/2 (MAPK pathway) but not of Akt (PI3K pathway). We conclude that the endogenous gastrin promoter is responsive to zinc ions, likely via activation of the MAPK pathway.
    Metallomics 09/2015; 7(10). DOI:10.1039/c5mt00147a · 3.59 Impact Factor
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    Dannel Yeo · Hong He · Graham Baldwin · Mehrdad Nikfarjam ·

    Pancreatology 06/2015; 15(3):S36. DOI:10.1016/j.pan.2015.05.155 · 2.84 Impact Factor
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    Dannel Yeo · Hong He · Graham S Baldwin · Mehrdad Nikfarjam ·
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    ABSTRACT: Pancreatic cancer is an aggressive cancer with a poor prognosis and an overall 5-year survival rate of less than 5%. Management has not improved significantly over the last 30 years, and a better understanding of the genetic and molecular changes that occur is urgently required. Many of these changes appear to involve the p21-activated kinases (PAKs). The PAK family consists of 6 isoforms, 2 of which, PAK1 and PAK4, are up-regulated and/or hyperactivated in pancreatic cancer. p21-Activated kinases can mediate many different cellular processes especially those contributing to cancer development and progression. These processes include the regulation of cytoskeletal dynamics and cell adhesion, the evasion of apoptosis, and the promotion of cell survival, proliferation, migration, and invasion. p21-Activated kinases may also be involved in characteristics unique to pancreatic tumors, such as interplay with the pancreatic stroma, the re-emergence of embryonic pathways, and the involvement of a subset of microRNAs and heat shock proteins. This review highlights the potential role of PAKs in pancreatic cancer and provides a foundation for more effective therapeutics to improve our current treatment of pancreatic cancer.
    Pancreas 04/2015; 44(3):363-9. DOI:10.1097/MPA.0000000000000276 · 2.96 Impact Factor
  • Marie Laval · Graham S Baldwin · Arthur Shulkes · Kathryn M Marshall ·
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    ABSTRACT: Hypoxia, or a low concentration of oxygen, is encountered in humans undertaking activities such as mountain climbing and scuba diving, and is important pathophysiologically as a limiting factor in tumor growth. Although data on the interplay between hypoxia and gastrins are limited, gastrin expression is upregulated by hypoxia in gastrointestinal cancer cell lines, and gastrins counterbalance hypoxia by stimulating angiogenesis in vitro and in vivo. The aim of this study was to determine if higher concentrations of the gastrin precursor progastrin are protective against hypoxia in vivo. hGAS mice, which over-express progastrin in the liver, and mice of the corresponding wild-type FVB/N strain, were exposed to normoxia or to hypoxia. Iron status was assessed by measurement of serum iron parameters, by real-time PCR for mRNAs encoding critical iron regulatory proteins, and by Perls' stain and atomic absorption spectrometry for tissue iron concentrations. FVB/N mice lost weight at a faster rate and had higher sickness scores than hGAS mice under hypoxia. Serum iron levels were lower in hGAS mice than in FVB/N mice and decreased further when exposed to hypoxia. The concentration of iron in the livers of hGAS mice was strikingly lower than in FVB/N mice. We conclude that increased circulating concentrations of progastrin provide a physiological advantage against systemic hypoxia in mice, possibly by increasing the availability of iron stores. This is the first report of an association between progastrin overexpression, hypoxia and iron homeostasis.
    AJP Gastrointestinal and Liver Physiology 11/2014; 308(2):ajpgi.00344.2014. DOI:10.1152/ajpgi.00344.2014 · 3.80 Impact Factor
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    Nhi Huynh · John A. Beutler · Arthur Shulkes · Graham S. Baldwin · Hong He ·
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    ABSTRACT: p-21-Activated kinase 1 (PAK1) enhances colorectal cancer (CRC) progression by stimulating Wnt/β-catenin, ERK and AKT pathways. PAK1 also promotes CRC survival via up-regulation of hypoxia-inducible factor 1α (HIF-1α), a key player in cancer survival. Glaucarubinone, a quassinoid natural product, inhibits pancreatic cancer growth by down-regulation of PAK1. The aim of this study was to investigate the effect of glaucarubinone on CRC growth and metastasis, and the mechanism involved. Cell proliferation was measured in vitro by [3H]-thymidine incorporation and in vivo by volume of tumor xenografts. Protein concentrations were measured by Western blotting of cell extracts. We report here that glaucarubinone inhibited CRC growth both in vitro and in vivo. The potency of glaucarubinone as an inhibitor of cell proliferation was negatively correlated to PAK1 expression in CRC cells. Glaucarubinone suppressed the expression of HIF-1α and β-catenin. Knockdown of PAK1 by shRNA enhanced inhibition by glaucarubinone while constitutively active PAK1 blocked the inhibitory effect. Our findings indicate that glaucarubinone inhibited CRC growth by down-regulation of HIF-1α and β-catenin via a PAK1-dependent pathway.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 10/2014; 1853(1). DOI:10.1016/j.bbamcr.2014.10.013 · 5.02 Impact Factor
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    ABSTRACT: Hypoxia-inducible factor 1α (HIF1α) over-expression has been correlated with poor prognosis in a number of cancers. Although it is widely accepted that hypoxia-induced up-regulation of HIF1α expression occurs by reduction in oxygen-dependent degradation, up-regulation of HIF1α under normoxic conditions is being demonstrated with increasing frequency in many cancers. We review the current knowledge of mechanisms of normoxic and hypoxic up-regulation of HIF1α and its therapeutic implications, with a particular focus on its role as a potential biomarker in prostate cancer (PC). Although the literature regarding the role of HIFs in cancer development and progression has been reviewed extensively, publications' specifically considering the role of HIFs in prostate cancer is sparse. Therefore Pubmed and Google searches with the keywords prostate cancer, castration resistance, metastasis, hypoxia, HIF1α, HIF2α and regulation were performed. Relevant articles including original research papers and reviews were selected based on their contents and a synopsis was generated. Normoxic expression of HIF1α plays an important role in the development of chemo-resistance, radio-resistance and castrate resistance of PC and HIF1α could thus be used as a potential biomarker. Furthermore, agents that target HIF1α could be used in adjuvant therapies in order to reduce resistance to conventional therapeutic modalities. Over-expression of HIF1α in PC can be regulated at the three levels of transcription, translation and protein stability, via a number of different mechanisms including gene amplification, single nucleotide polymorphism, increased transcription of HIF1α mRNA, expression of truncated isoforms of HIF1α and stabilization of HIF1α. However there is no definitive consensus and the intriguing question of how HIF1α is upregulated in PC is still unanswered. Over-expression of HIF1α under normoxia could be used as a biomarker for development of chemo-resistance, radio-resistance and castrate resistance in PC. There is an urgent need to identify the cause of over-expression of HIF1α in castrate-resistant PC cells and tumors, in order to guide the choice of HIF inhibitors (transcription- or translation-based) best suited for the treatment of castrate-resistant PC. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
    The Journal of Urology 10/2014; 193(3). DOI:10.1016/j.juro.2014.10.085 · 4.47 Impact Factor
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    ABSTRACT: Objective To determine the expression and biology of the neuroendocrine growth factor gastrin-releasing peptide (GRP) and other proGRP-derived peptides in renal cancer.Materials and methodsReceptor binding studies, ELISA and radioimmunoassay were used to quantitate the presence of proGRP-derived peptide receptors and their ligands in renal cancer cell lines and human renal cancers.Biological activity of proGRP peptides was confirmed with proliferation, migration, and ERK1/2 activation assays in vitro. In vivo, ACHN renal cancer xenografts were treated with proGRP-derived peptides to assess tumour size and necrosis. HIF1α and VEGF expression was investigated with western blotting and ELISA respectively to determine the possible contribution of the proGRP peptides to tumour viability.ResultsIn ACHN cells that express both proGRP- and GRP-receptors, the expression of proGRP binding sites was 80 fold greater than the GRP-receptor (GRPR).C-terminal proGRP-derived peptides stimulated the activation of ERK1/2, but with a different time course to GRP, consistent with the suggestion that these peptides may have unique cellular functions.Both GRP and proGRP47-68 stimulated proliferation and migration of ACHN cells in vitro, but only GRP reduced the extent of tumor necrosis in ACHN xenografts.GRP, but not proGRP47-68, was able to induce HIF1α and VEGF expression in ACHN cells. This may account in part for the reduction in necrosis following GRP treatment.C-terminal proGRP-derived peptides were present in all three renal cancer cell lines and a panel of human renal cancers, but mature amidated GRP was absent.ConclusionC-terminal proGRP peptides are more abundant in renal cancers and their cell lines than the more extensively studied amidated peptide, GRP. These results suggest that C-terminal proGRP-derived peptides may be a better target for novel renal cancer treatments.
    BJU International 08/2014; 115(5). DOI:10.1111/bju.12886 · 3.53 Impact Factor
  • David A. Westwood · Oneel Patel · Graham S Baldwin ·
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    ABSTRACT: Aim: Gastrins act as growth factors for the normal and neoplastic colorectal mucosa. The aim of this study was to determine the role of gastrins in the response of human colorectal cancer (CRC) cells to hypoxia in vitro and in vivo. Methods: Expression of the gastrin gene in the human CRC cell line LoVo was examined under normoxia and hypoxia by quantitative PCR and by radioimmunoassay. Gastrin expression was knocked down with shRNA, and the effect on cell proliferation was measured by cell counting, on cell apoptosis by annexin V staining, and on cell migration by Boyden chamber assay. The effect of gastrin knockdown on tumourigenesis in mouse xenografts was analysed by measurement of tumour volumes and weights, and by immunohistochemistry. Results: Gastrin gene expression in LoVo cells was stimulated by hypoxia via binding of hypoxia-inducible factor-1α to the gastrin promoter. The viability of gastrin knockdown cells exposed to hypoxia (1% O2) in vitro was diminished because of loss of resistance against hypoxia-induced apoptosis, and the effect was partly reversed by treatment with non-amidated, but not amidated, gastrin. Conditioned medium from control LoVo cells under hypoxia simulated proliferation but not migration, and the effect was blocked by an inhibitor of non-amidated gastrins, but not by an inhibitor of amidated gastrins. In xenografts in mice exposed to hypoxia (10% O2) for 21days, tumour necrosis was significantly increased by knocking down gastrin expression. Conclusion: These results provide evidence that non-amidated gastrins are involved in the adaptation of CRCs to hypoxic microenvironments through increasing resistance to apoptosis.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 07/2014; 1843(11). DOI:10.1016/j.bbamcr.2014.06.016 · 5.02 Impact Factor

  • Nature Reviews Urology 07/2014; 11(7). DOI:10.1038/nrurol.2013.110-c2 · 4.84 Impact Factor
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    Nhi Huynh · Kevin H. Liu · Mildred Yim · Arthur Shulkes · Graham S. Baldwin · Hong He ·
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    ABSTRACT: Gastrins, including amidated gastrin17 and glycine-extended gastrin17, are important growth factors in colorectal cancer (CRC). The p21-activated kinase 1 (PAK1) plays key roles in cellular processes including proliferation, survival, and motility, and in cell transformation and tumor progression. PAK1 expression increases with the progression of CRC, and knockdown of PAK1 blocks CRC cell growth and metastasis both in vitro and in vivo. The aim of this study was to determine the interaction between PAK1 and gastrins in CRC cells. PAK1 expression and activation were assayed by Western blots, and concentrations of gastrin mRNA and peptides by real-time PCR and radioimmunoassay, respectively. Proliferation of CRC cells was measured by 3H-thymidine incorporation, and vascular endothelial growth factor (VEGF) secretion was measured by ELISA. Gastrins activated PAK1 via PI3K-dependent pathways. Activated PAK1 in turn mediated gastrin-stimulated activation of β-catenin and VEGF secretion in CRC cells, as knockdown of PAK1 blocked stimulation of these cellular processes by gastrins. Downregulation of gastrin reduced the expression and activity of PAK1, but in contrast there was a compensatory increase in gastrins either when PAK1 was downregulated, or after treatment with a PAK inhibitor. Our results indicate that PAK1 is required for the stimulation of CRC cells by gastrins, and suggest the existence of an inhibitory feedback loop by which PAK1 downregulates gastrin production in CRC cells.
    06/2014; 2(6). DOI:10.14814/phy2.12048

  • The Journal of Urology 04/2014; 191(4):e508. DOI:10.1016/j.juro.2014.02.1118 · 4.47 Impact Factor
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    ABSTRACT: Expression of hypoxia-inducible factor (HIF)1α increases the risk of castrate-resistant prostate cancer (CRPC) and metastases in patients on androgen deprivation therapy (ADT) for prostate cancer (PC). We aimed to investigate the effects of nonspecific HIF1α inhibitors (Digoxin, metformin, and angiotensin-2 receptor blockers) on development of CRPC and metastases while on ADT. A retrospective review of prospectively collected medical records was conducted of all men who had continuous ADT as first-line therapy for CRPC at the Austin Hospital from 1983 to 2011. Association between HIF1α inhibitor medications and time to develop CRPC was investigated using actuarial statistics. Ninety-eight patients meeting the criteria were identified. Eighteen patients (21.4%) were treated with the nonspecific HIF1α inhibitors. Both groups had similar characteristics, apart from patients on HIF1α inhibitors being older (70 years vs. 63.9 years). The median CRPC-free survival was longer in men using HIF1α inhibitors compared to those not on inhibitors (6.7 years vs. 2.7 years, P = 0.01) and there was a 71% reduction in the risk of developing CRPC (HR 0.29 [95% CI 0.10-0.78] P = 0.02) after adjustment for Gleason score, age, and prostate-specific antigen (PSA). The median metastasis-free survival in men on HIF1α inhibitors was also significantly longer compared to those on no inhibitors (5.1 years vs. 2.6 years, P = 0.01) with an 81% reduction in the risk of developing metastases (HR 0.19 [CI 0.05-0.76] P = 0.02) after adjustment for Gleason score, age, and PSA. Nonspecific HIF1α inhibitors appear to increase the progression-free survival and reduce the risk of developing CRPC and metastases in patients on continuous ADT.
    Cancer Medicine 04/2014; 3(2). DOI:10.1002/cam4.189 · 2.50 Impact Factor
  • K. Rao · M. Yim · D. Bolton · L. Galea · G. Baldwin · A. Shulkes · O. Patel ·

    European Urology Supplements 04/2014; 13(1):e914. DOI:10.1016/S1569-9056(14)60900-3 · 3.37 Impact Factor
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    Hong He · Mehrdad Nikfarjam · Dannel Yeo · Xiao Wang · Nhi Huynh · Graham S. Baldwin ·

    Pancreatology 03/2014; 14(2):S4. DOI:10.1016/j.pan.2014.04.008 · 2.84 Impact Factor
  • Joseph Ischia · Oneel Patel · Damien Bolton · Arthur Shulkes · Graham S Baldwin ·
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    ABSTRACT: Gastrin-releasing peptide (GRP) acts as an important regulatory peptide in several normal physiological processes and as a growth factor in certain cancers. In this review we provide a comprehensive overview of the current state of knowledge of GRP in urological tissues under both normal and cancerous conditions. GRP and its receptor, GRP-R, are expressed in the normal kidney and renal cancers. GRP can stimulate the growth of renal cancer cells. GRP and GRP-R are expressed in prostate cancer and GRP can stimulate the growth of prostate cancer cell lines. Importantly, GRP is a key neuroendocrine peptide, which may be involved in the progression of advanced prostate cancer and in the neuroendocrine differentiation of prostate cancer. Recent animal studies have shown that GRP and GRP-R are an integral part of male sexual function and play a crucial role in spinal control of erections and ejaculation.
    BJU International 03/2014; 113 Suppl 2(S2):40-7. DOI:10.1111/bju.12594 · 3.53 Impact Factor
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    ABSTRACT: An increase in circulating concentrations of gastrin or gastrin precursors such as progastrin and glycine-extended gastrin has been proposed to promote the development of colorectal carcinomas (CRC). The aim of this study was to investigate whether or not circulating gastrin concentrations were increased in patients with an increased risk of developing CRC. Patients were divided according to their risk into the five following groups: familial adenomatous polyposis (n = 20), hereditary non-polyposis colorectal cancer (n = 53), cluster of common colorectal cancers (n = 13), personal history and/or family history of adenomatous polyps or CRC (n = 150) and controls (n = 42). Radioimmunoassay with four region-specific gastrin antisera was used to measure progastrin, glycine-extended gastrin (gastrin-gly), amidated gastrin (gastrin-amide), and total gastrin in peripheral blood taken at the time of colonoscopy. Compared with the control group, familial adenomatous polyposis patients had significantly higher median values of total gastrin (29.8 pM vs 16.9 pM, P = 0.003) and gastrin-amide (17.1 pM vs 12.0 pM, P = 0.015). Patients with a personal or family history of adenomatous polyps or CRC also had higher circulating concentrations of total gastrin (21.8 pM) compared with controls (P < 0.05), while patients from all groups who presented with an adenomatous polyp on the day of colonoscopy had higher concentrations of total gastrin, progastrin, and gastrin-amide than patients without polyps. Concentrations of gastrin precursors are increased in particular groups with an increased risk of developing CRC.
    Journal of Gastroenterology and Hepatology 03/2014; 29(3):480-6. DOI:10.1111/jgh.12417 · 3.50 Impact Factor
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    ABSTRACT: Pancreatic cancer is one of the most lethal of human malignancies. Nearly 100% cases of pancreatic cancer carry mutations in KRas. P-21-activated kinases (PAKs) are activated by and act downstream of KRas. Glaucarubinone, a natural product first isolated from the seeds of the tree Simarouba glauca, was originally developed as an antimalarial drug, and has more recently been recognised as an anticancer agent. The aims of this study were to determine whether glaucarubinone, alone or in combination with the front-line chemotherapeutic agent gemcitabine, would inhibit the growth of pancreatic cancer cells in vitro or in vivo and the mechanism involved. Growth of the human pancreatic cancer cell lines PANC-1 and MiaPaCa-2 was measured by (3)H-thymidine incorporation in vitro, and by volume as xenografts in SCID mice. The expression and activities of the two serine/threonine kinases PAK1 and PAK4, which are key regulators of cancer progression, were measured by Western blotting. Here we report that glaucarubinone decreased proliferation and migration of pancreatic cancer cells in vitro, and reduced their growth as xenografts in vivo. Treatment with glaucarubinone and gemcitabine reduced proliferation in vitro and tumour growth in vivo more than treatment with either glaucarubinone or gemcitabine alone. Treatment with glaucarubinone reduced PAK1 and PAK4 activities, which were further decreased by the combination of glaucarubinone and gemcitabine. These results indicate that glaucarubinone reduced pancreatic cancer cell growth at least in part via inhibition of pathways involving PAK1 and PAK4. The synergistic inhibition by glaucarubinone and gemcitabine observed both in vitro and in vivo suggests that glaucarubinone may be a useful adjunct to current regimes of chemotherapy.
    Cancer letters 01/2014; 346(2). DOI:10.1016/j.canlet.2014.01.001 · 5.62 Impact Factor
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    Lin Xiao · Suzana Kovac · Mike Chang · Arthur Shulkes · Graham S Baldwin · Oneel Patel ·
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    ABSTRACT: Gastrin and its precursors act as growth factors for the normal and neoplastic gastrointestinal mucosa. As the hypoxia mimetic cobalt chloride upregulates the gastrin gene, the effect of other metal ions on gastrin promoter activity was investigated. Gastrin mRNA was measured by real-time PCR, gastrin peptides by RIA, and gastrin promoter activity by dual-luciferase reporter assay. Exposure to Zn(2)(+) ions increased gastrin mRNA concentrations in the human gastric adenocarcinoma cell line AGS in a dose-dependent manner, with a maximum stimulation of 55±14-fold at 100 μM (P<0.05). Significant stimulation was also observed with Cd(2)(+) and Cu(2)(+), but not with Ca(2)(+), Mg(2)(+), Ni(2)(+), or Fe(3)(+) ions. Activation of MAPK and phosphatidylinositol 3-kinase pathways is necessary but not sufficient for gastrin induction by Zn(2)(+). Deletional mutation of the gastrin promoter identified an 11 bp DNA sequence, which contained an E-box motif, as necessary for Zn(2)(+)-dependent gastrin induction. The fact that E-box binding transcription factors play a crucial role in the epithelial-mesenchymal transition (EMT), together with our observation that Zn(2)(+) ions upregulate the gastrin gene in AGS cells by an E-box-dependent mechanism, suggests that Zn(2)(+) ions may induce an EMT, and that gastrin may be involved in the transition.
    Journal of Molecular Endocrinology 01/2014; 52(1):29-42. DOI:10.1530/JME-13-0162 · 3.08 Impact Factor

Publication Stats

3k Citations
856.58 Total Impact Points


  • 1979-2015
    • University of Melbourne
      • Department of Surgery
      Melbourne, Victoria, Australia
  • 1998-2014
    • Victoria University Melbourne
      Melbourne, Victoria, Australia
  • 1996-2005
    • Austin Health
      Melbourne, Victoria, Australia
  • 2000
    • Diabetes Australia, Victoria
      Melbourne, Victoria, Australia
    • Université Montpellier
      • Faculté de Pharmacie
      Montpelhièr, Languedoc-Roussillon, France
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1982-1998
    • Ludwig Institute for Cancer Research Australia
      Melbourne, Victoria, Australia
  • 1984-1996
    • Royal Melbourne Hospital
      • Department of Radiology
      Melbourne, Victoria, Australia
  • 1991-1995
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
  • 1988
    • Ludwig Institute for Cancer Research Brazil
      San Paulo, São Paulo, Brazil