The role of the essential biometal zinc in pathological and physiological processes

• 
  
  Dr Oneel Patel
  Dr Joseph Ischia

  patelo@unimelb.edu.au

  View researcher's webpage

  +61 3 9496 3676

• 
  Professor
  Graham Baldwin

  grahamsb@unimelb.edu.au

  View researcher's webpage

  +61 3 9496 5592

Project Details

Zinc (Zn) is the second most abundant biometal after iron in the body. Zn is essential for various process such as cell proliferation, cell cycle regulation, differentiation and apoptosis, the functioning of Zn-finger transcription factors, the regulation of energy metabolism, the epithelial-mesenchymal transition (EMT) and activation of the transcription factor hypoxia-inducible factor-1α (HIF1α). We are examining whether dysregulation of Zn homeostasis and a consequent increase in intracellular free Zn ions stimulates proliferation and migration, and modulates glycolysis, EMT and the expression of HIF1α in various cancer cells and tumours, which in turn escalates cancer progression. We are exploring the option of using Zn chelation as a new treatment for cancers of diverse origin including the gastrointestinal tract, the prostate, and the kidney.

Ischaemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) in multiple surgeries including partial nephrectomy (PN) for kidney cancer and renal transplantation. Although a large number of drugs and agents have been shown to protect against IRI in renal, myocardial and neuronal tissue in vitro and in vivo (rat or mouse), all have failed in either pre-clinical large animal model or human trials. We have now shown using animal models (rat and sheep) and human kidney cells that pre-treatment with Zn ameliorates IRI by 70%. We are now exploring the following key remaining questions. How does Zn mitigate IRI? Can we extrapolate the use of Zn to other injuries that exhibit mechanisms similar to IRI such as contrast-induced nephropathy?

Researchers

• Professor Graham S Baldwin
• Dr. Joseph Ischia, Surgeon
• Dr. Oneel Patel, Research Fellow

Collaborators

• Professor Damien Bolton

Funding

NHMRC

Austin Medical Research Foundation

Research Outcomes

1. Ranasinghe WK, Baldwin GS, Bolton D, Shulkes A, Ischia J, and Patel O. 2015 HIF1alpha expression under normoxia in prostate cancer--which pathways to target?  J Urol 193(3): 763-770.
2. Marshall KM, Laval M, Estacio O, Hudson DF, Kalitsis P, Shulkes A, Baldwin GS, and Patel O. 2015 Activation by zinc of the human gastrin gene promoter in colon cancer cells in vitro and in vivo.  Metallomics 7(10): 1390-1398.
3. Ischia J, Patel O, Sethi K, Nordlund MS, Bolton D, Shulkes A, and Baldwin GS. 2015 Identification of binding sites for C-terminal pro-gastrin-releasing peptide (GRP)-derived peptides in renal cell carcinoma: a potential target for future therapy.  BJU Int 115(5): 829-838.
4. Xiao L, Kovac S, Chang M, Shulkes A, Baldwin GS, and Patel O. 2014 Zinc ions upregulate the hormone gastrin via an E-box motif in the proximal gastrin promoter.  J Mol Endocrinol 52(1): 29-42.
5. Rao K, Yim M, Bolton D, Galea L, Baldwin G, Shulkes A, and Patel O. 2014 Zinc preconditioning protects the rat kidney against ischemic injury.  Eur Urol Suppl 13(13): e914.
6. Ranasinghe WK, Sengupta S, Williams S, Chang M, Shulkes A, Bolton DM, Baldwin G, and Patel O. 2014 The effects of nonspecific HIF1alpha inhibitors on development of castrate resistance and metastases in prostate cancer.  Cancer Med 3(2): 245-251.
7. Ranasinghe WK, Baldwin GS, Shulkes A, Bolton D, and Patel O. 2014 Normoxic regulation of HIF-1alpha in prostate cancer.  Nat Rev Urol 11(7): 419.
8. Ischia J, Patel O, Bolton D, Shulkes A, and Baldwin GS. 2014 Expression and function of gastrin-releasing peptide (GRP) in normal and cancerous urological tissues.  BJU Int 113 Suppl 2: 40-47.
9. Ranasinghe WK, Xiao L, Kovac S, Chang M, Michiels C, Bolton D, Shulkes A, Baldwin GS, and Patel O. 2013 The role of hypoxia-inducible factor 1alpha in determining the properties of castrate-resistant prostate cancers.  PLoS ONE 8(1): e54251.
10. Xiao L, Kovac S, Chang M, Shulkes A, Baldwin GS, and Patel O. 2012 Induction of gastrin expression in gastrointestinal cells by hypoxia or cobalt is independent of hypoxia-inducible factor (HIF).  Endocrinology 153(7): 3006-3016.

Research Publications

1. Marshall KM, Laval M, Estacio O, Hudson DF, Kalitsis P, Shulkes A, Baldwin GS, Patel O. Activation by zinc of the human gastrin gene promoter in colon cancer cells in vitro and in vivo. Metallomics. 2015 Oct;7(10):1390-8.
2. Ranasinghe WK, Baldwin GS, Bolton D, Shulkes A, Ischia J, Patel O. HIF1α Expression under Normoxia in Prostate Cancer- Which Pathways to Target? J Urol. 2014 Oct 19. pii: S0022-5347(14)04766-1
3. Ranasinghe WK, Xiao L, Kovac S, Chang M, Michiels C, Bolton D, Shulkes A, Baldwin GS, Patel O. The role of hypoxia-inducible factor 1alpha in determining the properties of castrate-resistant prostate cancers. PLOS One 2013;8(1):e54251.
4. Xiao L, Kovac S, Chang M, Shulkes A, Baldwin GS, Patel O. Zinc ions upregulate the hormone gastrin via an E-box motif in the proximal gastrin promoter. J Mol Endocrinol 2014;52(1):29-42.
5. Xiao L, Kovac S, Chang M, Shulkes A, Baldwin GS, Patel O. Induction of gastrin expression in gastrointestinal cells by hypoxia or cobalt is independent of hypoxia-inducible factor (HIF). Endocrinology 2012;153(7):3006-16.