The role of oxysterol binding protein-related protein 5 in pancreatic cancer.
The expression of oxysterol binding protein-related protein (ORP) 5 is related to invasion and a poor prognosis in pancreatic cancer patients. ORP5 induced the expression of sterol response element binding protein (SREBP) 2 and activated the downstream gene of sterol response element. ChIP using SREBP2 antibody revealed that histone deacetylase 5 (HDAC5) was one of the downstream genes of SREBP2. The effect of HMG-CoA reductase inhibitors (statins) were analyzed according to the expression level of ORP5. The invasion rate and growth was suppressed in cells that strongly expressed ORP5 in a time- and dose-dependent manner, but had less effect in cells weakly expressing ORP5, suggesting that when the potential of invasion and growth relies on the cholesterol synthesis pathway, it becomes sensitive to HMG-CoA reductase inhibitor. Furthermore, HDAC inhibitor, tricostatin A, induced the expression of phosphatase and tensin homolog as well when ORP5 was suppressed or the cells were treated with statin. Treatment with both statin and tricostatin A showed a synergistic antitumor effect in cells that highly expressed ORP5. Therefore, in some pancreatic cancers, continuous ORP5 expression enhances the cholesterol synthesis pathway and this signal transduction regulates phosphatase and tensin homolog through HDAC5 expression. This is the first report to detail how the signal transduction of cholesterol synthesis is related to cancer invasion and why statins can suppress invasion and growth.
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Shinji
S
Ishikawa
Youhei
Y
Nagai
Toshirou
T
Masuda
Yoshikatsu
Y
Koga
Tadahiko
T
Nakamura
Yu
Y
Imamura
Hiroshi
H
Takamori
Masahiko
M
Hirota
Akihiro
A
Funakosi
Masakazu
M
Fukushima
Hideo
H
Baba
D000924:Anticholesteremic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000502:physiology*; D019821:Simvastatin / Q000494:pharmacology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D000098825:Oxysterol Binding Proteins
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011987:Receptors, Steroid; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D000098825:Oxysterol Binding Proteins; D019821:Simvastatin; C404500:HDAC5 protein, human; D006655:Histone Deacetylases