Overexpression of hepatocyte nuclear factor-3alpha induces apoptosis through the upregulation and accumulation of cytoplasmic p53 in prostate cancer cells.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Hyun Joo
HJ
Lee
Soma
S
Chattopadhyay
Wan-Hee
WH
Yoon
Jong Yoon
JY
Bahk
Tae-Hyoung
TH
Kim
Hyung Sik
HS
Kang
Keesook
K
Lee
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D003593:Cytoplasm; D004789:Enzyme Activation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D051541:Hepatocyte Nuclear Factor 3-alpha; D016159:Tumor Suppressor Protein p53; D020169:Caspases