c-Abl kinase regulates curcumin-induced cell death through activation of c-Jun N-terminal kinase.
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.
Kamath
Ravindra
R
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1205 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
Jiang
Zhihua
Z
Sun
Guoming
G
Yalowich
Jack C
JC
Baskaran
R
R
D001549:Benzamides; D016923:Cell Death / Q000187:drug effects*; D002467:Cell Nucleus / Q000201:enzymology; D003474:Curcumin / Q000494:pharmacology*; D003593:Cytoplasm / Q000201:enzymology; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D000068877:Imatinib Mesylate; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007700:Kinetics; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D048031:JNK Mitogen-Activated Protein Kinases; D003474:Curcumin