Molecular mechanism for the regulation of zinc transport by protein kinase CK2

Abstract

Breast and prostate cancers are the most common cancers in Australian women and men, respectively. The dysregulation of zinc (Zn2+) homeostasis is an intriguing hallmark for both cancers, e.g., hyper-accumulation of Zn2+ in breast cancer compared to normal breast tissue and low level of cellular Zn2+ in prostate cancer in comparison to normal prostate tissue. Such opposite profiles of zinc in breast and prostate cancer cells point to the potential involvement of zinc in cancer development. This study takes advantage of such characteristic feature between breast and prostate cancer cells to explore their molecular details in zinc homeostasis. In this study, protein kinase CK2 (CK2) was firstly analysed in breast and prostate cancer cells, by dissecting the distinct roles of CK2 subunits (CK2a, CK2a' and CK2B) in zinc homeostasis. Using CK2 inhibitors 4,5,6,7-tetrabromobenzotriazole (TBB) and CX-4945, siRNA-mediated knockdown and zinc ion specific fluorophores (FluoZin-3 AM), this study demonstrated that zinc accumulation was elevated in PC3 and DU145 prostate cancer cells due to knockdown of the gene expression for CK2a', while the opposite was observed in MCF-7 and MDA-MB-231 breast cancer cells. Furthermore, siRNA knockdown of individual CK2 subunits showed that individual subunits of CK2 have distinct roles in zinc homeostasis in breast and prostate cancer cells. These findings demonstrated that CK2 is indeed involved in zinc homeostasis in breast and prostate cancer cells, as well as that of individual CK2 subunits play distinct roles. The results of this study demonstrated the involvement of CK2 in zinc homeostasis in breast and prostate cancer cells. The RNA-seq dataset confers a holistic view at the molecular level on how the cancer cell responds to the extracellular zinc exposure. The findings of this study provide molecular insights into zinc homeostasis of breast and prostate cancer cells. As zinc is critical for the structure and function of ~3000 human proteins, the molecular details described in this thesis should open multitudes of avenues for cancer research and anti-cancer drug development.

Date of Award	2021
Original language	English