Abstract
Curcumin, a natural phenolic compound found in turmeric (Curcuma longa) exhibits anticancer properties, attributed to its antiproliferative and apoptosis-inducing activity. The ubiquitously expressed nonreceptor tyrosine kinase c-Abl regulates stress responses induced by oxidative agents such as ionizing radiation and H2O2. In this study, we show that c-Abl is an important component of the cell death response activated by curcumin and that Abl mediates this response partly through activation of c-Jun N-terminal kinase (JNK). Therefore, inhibition of Abl by STI571 [imatinib (Gleevec)] treatment or down-regulation of Abl expression through Abl-specific short-hairpin RNA (shRNA) diminished cell death induction and JNK activation. Highlighting the interdependent nature of the Abl and JNK signaling in the curcumin-induced cell death response, a JNK inhibitor [anthra(1,9-cd)pyrazol-6(2H)-one-1,9-pyrazoloanthrone (SP600125)] caused very little cell death inhibition in STI571-pretreated cells and in Abl shRNA-expressing cells. Moreover, treatment with Abl and JNK inhibitor alone or together caused similar levels of cell death inhibition. Although p53 induction in response to curcumin treatment is dependent on Abl, we found that Abl→p53 signaling is not necessary for curcumin-induced cell death. Taken together, the results demonstrate the differential roles played by Abl→p53 and Abl→JNK signaling events in modulating the cell death response to curcumin.
Footnotes
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This work was supported in part by National Institutes of Health grants GM60945 (to R.B) and CA90787 (to J.C.Y).
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ABBREVIATIONS: NF-κB, nuclear factor-κB; JNK, c-Jun N-terminal kinase; SP600125, anthra(1,9-cd)pyrazol-6(2H)-one-1,9-pyrazoloanthrone; ROS, reactive oxygen species; CTD, C-terminal domain; MEK, mitogen-activated protein kinase kinase; DMSO, dimethyl sulfoxide; STI571, imatinib; DCFH-DA 2′,7′-dichlorofluorescein diacetate; PARP, poly(ADP-ribose) polymerase; PBS, phosphate-buffered saline; GST, glutathione transferase; IP, immunoprecipitation; NAC, N-acetyl cysteine; CurC, curcumin; shRNA, short hairpin RNA.
- Received May 11, 2006.
- Accepted October 3, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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