Overexpression of hepatocyte nuclear factor‐3α induces apoptosis through the upregulation and accumulation of cytoplasmic p53 in prostate cancer cells

Abstract

Hepatocyte nuclear factor-3alpha (HNF-3alpha) has been known to act as a repressor in the pathogenesis of many cancers. Herein, we investigated the effect of HNF-3alpha overexpression in prostate cancer cells. HNF-3alpha was overexpressed in prostate cancer cells using an adenovirus recombinant expressing wild-type HNF-3alpha. The apoptosis of prostate cancer cells was determined by TUNEL, FACS, and caspase activity analyses. Adenovirus-mediated overexpression of HNF-3alpha caused cell death in prostate cancer cells as assessed by changes in cellular and nuclear morphology, TUNEL analysis, and caspase activations. Furthermore, FACS analysis showed an increased sub-G1 phase of cell cycle as well as the G2/M phase with a corresponding decrease in S phases. HNF-3alpha overexpression caused the upregulation of p53 protein and its accumulation, together with HNF-3alpha, in the cytoplasm. It also causes Bax protein to localize to the mitochondria-enriched fraction. These findings suggest that multiple apoptotic pathways seem to be involved in the HNF-3alpha-induced cell death: pathways involving the accumulation of p53 protein in the cytoplasm and subsequent cytochrome c release, and other pathways involving death receptor signaling and caspase-8 activation. The results of the current study suggest a novel function of HNF-3alpha as a killer of malignant prostate cancer cells, which reveals HNF-3alpha as a promising therapeutic molecule for prostate cancers.