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Molecular Mechanisms of Par-4-Induced Apoptosis in Prostate Cancer

Abstract : The prostate apoptosis response-4 (Par-4) protein induces apoptosis in prostate cancer cells but not in normal cells. The region spanning residues 145-203 of human Par-4 kills androgen-dependent and androgen-independent cancer cells but not normal cells, and is termed selective for apoptosis induction in cancer cells (SAC) domain. Par-4 also contains a C-terminal coiled-coil (CC) domain that interacts with the protein kinase Akt1 and the DNA-binding domain of WT1. Phosphorylation of Par-4 by Akt1 results in inhibition of apoptosis. To obtain insights into the mechanisms of Par-4 selective killing of prostate cancer cells, we expressed the human Par-4 SAC domain in bacteria and purified it to homogeneity. Numerous attempts to crystallize this protein in the apo form failed to yield diffraction-quality crystals. Analysis of the SAC domain using NMR spectroscopy revealed that it is unstructured, demonstrating the need to perform a structural analysis of this domain bound to its binding partner, where SAC will likely adopt a structure. The structures of Par-4 SAC and CC domains will facilitate the elucidation of the mechanisms underlying the selective killing of prostate cancer cells by this protein and will guide the development of novel molecular targeted therapies for prostate cancer.