Abstract
Activation of pancreatic stellate cells (PSCs) is the key process in the development of pancreatic fibrosis, a common feature of chronic pancreatitis and pancreatic cancer. In recent studies, curcumin has been shown to inhibit PSC proliferation via an extracellular signal-regulated kinase (ERK)1/2-dependent mechanism. In addition, curcumin is a potent inducer of the cytoprotective enzyme heme oxygenase-1 (HO-1) in other cell types. Therefore, the aims of this study were to 1) characterize the effect of curcumin on HO-1 gene expression in PSCs, 2) explore whether HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation, and 3) clarify the involvement of the mitogen-activated protein kinase (MAPK) family in this context. Cultured rat PSCs were incubated with curcumin and assessed for HO-1 up-regulation by Northern blot analysis, immunoblotting, and activity assays. The effect of HO-1 on platelet-derived growth factor (PDGF)-induced PSC proliferation and MAPK activation was determined by immunoblotting, cell proliferation assays, and cell count analyses. Curcumin induced HO-1 gene expression in PSCs in a time- and dose-dependent manner and inhibited PDGF-mediated ERK1/2 phosphorylation and PSC proliferation. These effects were blocked by treatment of PSCs with tin protoporphyrin IX, an HO inhibitor, or transfection of HO-1 small interfering RNA. Our data provide evidence that HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation. Therefore, therapeutic up-regulation of HO-1 could represent a mode for inhibition of PSC proliferation and thus may provide a novel strategy in the prevention of pancreatic fibrosis.
Footnotes
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Parts of this work were previously presented as follows: Schwer CI, Guerrero AM, Humar M, Geiger KK, Pannen BHJ, and Schmidt R (2007) Heme oxygenase-1 mediates the antiproliferative effect of curcumin on pancreatic stellate cells, in Heme Oxygenases; 5th International Meeting on Heme Oxygenases; 2007 Sept 5–9; Krakow, Poland.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.136549.
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ABBREVIATIONS: PSC, pancreatic stellate cell; PDGF, platelet-derived growth factor; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; HO, heme oxygenase; BrdU, 5-bromo-2′-deoxyuridine; SnPP, tin protoporphyrin IX; MAPKAPK-2, MAP kinase-activated protein kinase-2; IMDM, Iscove's modified Dulbecco's medium; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; MEK, mitogen/extracellular signal-regulated kinase kinase; PD98059, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; SB203580, 4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole; SP600125, anthra[1,9-cd]pyrazole-6 2H)-one; FCS, fetal calf serum; siRNA, small interfering RNA.
- Received January 15, 2008.
- Accepted September 9, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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