Metal Occupancy of Zinc Finger Motifs as Determinants for Zn2+-Mediated Chemosensitization of Prostate Cancer Cells
Abstract
The purpose of this project is to determine how changes in levels of Zn2+ affect the occupancy of proteins that include Zn2+ finger motifs and how in turn Zn2+ occupancy affects the function of prostate cancer cells and in particular response to chemotherapy. Our findings show that prostate cancer cells are highly sensitive to perturbations in Zn2+ concentration with both increases and decreases of Zn2+ causing cytotoxicity and increasing sensitivity to chemotherapy. Our studies showed that the effects of exogenous Zn2+ on prostate cancer viability were reversible and that cells adapted to changes in Zn2+ levels. In contrast, Zn2+ chelation was irreversible and led to apoptosis. For the chemotherapy drug-candidate F10 Zn2+ chelation was synergistic and has maximal effect when administered more than 24 h after treatment. A novel finding was that the serine protease Omi/HtrA2 enhanced F10-induced apoptosis in a Zn2+-dependent manner Treatment with F10 induced p53-responsive genes p21 and Bax in a Zn2+-dependent manner. Extensive molecular dynamics simulations were undertaken on the Zn2+-finger peptide from NEMO, a component of the NF-kB responsive pathway. These computational experiments revealed the free energy for Zn2+ dissociation from this peptide was ~2.5 kcal/mol. These experimental and computational studies will be pursued in future grant applications to develop a comprehensive understanding of the effects of Zn2+ levels on the response of prostate cancer cells to chemotherapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2013
- Accession Number
- ADA596731
Entities
People
- William H. Gmeiner
Organizations
- Wake Forest University