Abstract
In this study, we investigated the anticancer effect of protoapigenone on human prostate cancer cells. Protoapigenone inhibited cell growth through arresting cancer cells at S and G2/M phases as well as inducing apoptosis. Blockade of cell cycle by protoapigenone was associated with an increase in the levels of inactivated phospho (p)-Cdc25C (Ser216) and a decrease in the levels of activated p-cyclin B1 (Ser147), cyclin B1, and cyclin-dependent kinase (Cdk) 2. Protoapigenone triggered apoptosis by increasing the levels of cleaved poly(ADP-ribose) polymerase and caspase-3. In addition, activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK)1/2 was a critical mediator in protoapigenone-induced cell death. Inhibition of the expression of p38 MAPK and JNK1/2 by pharmacological inhibitors or specific small interfering RNA reversed the protoapigenone-induced apoptosis through decreasing the level of cleaved caspase-3. In contrast, p38 MAPK, but not JNK1/2, was involved in the protoapigenone-mediated S and G2/M arrest by modulating the levels of Cdk2 and p-Cdc25C (Ser216). Moreover, in vivo xenograft study showed that protoapigenone had a significant inhibition of prostate tumor growth without major side effects on the mice we tested. This inhibition was associated with induction of apoptosis and activation of p38 MAPK and JNK1/2 in protoapigenone-treated tumor tissues. In conclusion, our results demonstrated protoapigenone suppressed prostate cancer cell growth through the activation of p38 MAPK and JNK1/2, with the potential to be developed as a chemotherapeutic agent for prostate cancer.
Footnotes
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This work was supported by Grants NSC96-2628-B-037-002-MY3 (to J.-H.S.) and NSC96-2323-B-037-002 (to Y.-C.W.) from the National Science Council, Taiwan, Republic of China, and Grant NHRI-EX96-9306B1 (to S.-S.F.Y.) from National Health Research Institutes, Taiwan, Republic of China.
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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.107.135442.
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ABBREVIATIONS: PCA, prostate cancer; p38 MAPK, p38 mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; ERK, extracellular signal-regulated kinase; MKK, mitogen-activated protein kinase kinase; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinyl phenyl)-5-(4-yridyl)-1H-imidazole; SP600125, anthrax[1,9-cd]pyrazol-6(2H)-one-1,9-pyrazoloanthrone; PARP, poly(ADP-ribose) polymerase; Cdk, cyclin-dependent kinase; XTT, sodium 3-[1-(phenylamino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene-sulfonic acid hydrate; PBS, phosphate-buffered saline; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; siRNA, small interfering RNA; BUN, blood urea nitrogen; Cr, creatinine; FITC, fluorescein isothiocyanate.
- Received December 18, 2007.
- Accepted March 11, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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