Received for publication May 11, 2006.
Revised October 3, 2006.
Accepted for publication October 3, 2006.

c-Abl kinase regulates curcumin-induced cell death through activation of JNK

Abstract

Curcumin, a natural phenolic compound found in turmeric (curcuma longa) exhibits anti-cancer properties, attributed to its anti-proliferative and apoptosis-inducing activity. The ubiquitously expressed non-receptor tyrosine kinase, c-Abl regulates stress responses induced by oxidative agents such as ionizing radiation and H₂O₂. Here we show that c-Abl is an important component of the cell death response activated by curcumin and that Abl mediates this response, in part, through activation of JNK. Consequently, inhibition of Abl by STI571 (Imanitib, Gleevac) treatment or downregulation of Abl expression through Abl specific ShRNA diminished cell death induction and JNK activation. Highlighting the inter-dependent nature of the Abl and JNK signaling in the curcumin-induced cell death response, a JNK inhibitor (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 Ablp53 signaling is dispensable for curcumin-induced cell death. Taken together, the results demonstrate the differential roles played by Ablp53 and AblJNK signaling events in modulating the cell death response to curcumin.

Key words: Apoptosis, Oxidative stress/antioxidants, Mechanisms of cell killing/apoptosis

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