Targeting zinc signalling to prevent cell division in cancer

Zinc is the second most abundant trace element in the human body and several disease states have been attributed to zinc dysregulation. Recent evidence has shown that zinc is a second messenger with roles in a diverse range of cellular signalling pathways. Of particular interest, is the discovery that cells require zinc to enter mitosis (cell division) and that several zinc transporter proteins have increased expression in cancer, a disease of uncontrolled cell division. Furthermore, post-translational modification has been shown to play a role in ZIP transporter activity. Understanding ZIP transporter regulation in cell division is key to revealing the mechanisms of zinc signalling in cancer. A combination of molecular and cell biological techniques have been used in this project to understand the role of ZIP transporter post-translational modification in cell division and to characterise novel anti-ZIP antibodies for their potential to stop tumour growth. This project highlighted that ZIP10 undergoes ectodomain shedding in mitosis and in response to zinc availability; an important mechanism for maintaining cellular zinc homeostasis. Analysis of potential ZIP10 phospho-sites revealed the potential phosphorylation of ZIP10 on several residues in the loop between TMD3 and TMD4. Furthermore, the interaction of ZIP10 with cell cycle-regulated kinases including CDK1 and PLK1 in mitosis was demonstrated. In addition, novel antibodies against ZIP transporters ZIP6 and ZIP10, both of which have been implicated in several cancers, were developed and the work presented here demonstrated their ability to prevent cell division in breast cancer, prostate cancer and melanoma cell lines in vitro, and slow breast tumour growth in vivo. This project also provided the first indication that ZIP6- and ZIP10-mediated cell division is important for non-cancerous cells, supporting the evidence that zinc signalling mechanisms are vital to human health; a finding that is relevant to the wider field of cellular biology