Apoptosis by Par-4 in cancer and neurodegenerative diseases

Abstract

Prostate apoptosis response-4 (par-4) is a pro-apoptotic gene identified in prostate cancer cells undergoing apoptosis. Par-4 protein, which contains a leucine zipper domain at the carboxy-terminus, functions as a transcriptional repressor in the nucleus. Par-4 selectively induces apoptosis in androgen-independent prostate cancer cells and Ras-transformed cells but not in androgen-dependent prostate cancer cells or normal cells. Cells that are resistant to apoptosis by Par-4 alone, however, are greatly sensitized by Par-4 to the action of other pro-apoptotic insults such as growth factor withdrawal, tumor necrosis factor, ionizing radiation, intracellular calcium elevation, or those involved in neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and stroke. Apoptosis induction by Par-4 involves a complex mechanism that requires activation of the Fas death receptor signaling pathway and coparallel inhibition of cell survival NF-kappaB transcription activity. The unique ability of Par-4 to induce apoptosis in cancer cells but not normal cells and the ability of Par-4 antisense or dominant-negative mutant to abrogate apoptosis in neurodegenerative disease paradigms makes it an appealing candidate for molecular therapy of cancer and neuronal diseases.