c-Abl Kinase Regulates Curcumin-Induced Cell Death through Activation of c-Jun N-Terminal Kinase

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 H 2 O 2 . 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 downregulation 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 Abl3p53 signaling is not necessary for curcumin-induced cell death. Taken together, the results demonstrate the differential roles played by Abl3p53 and Abl3 JNK signaling events in modulating the cell death response to curcumin.

The Mismatch Repair System Modulates Curcumin Sensitivity through Induction of DNA Strand Breaks and Activation of G2-M Checkpoint

“…In addition, it has been determined that curcumin's anti-proliferative effect is attributable to sharp rise in superoxide anion concentrations in treated cells [16, 17]. Similarly, we observed that curcumin exposure results in increased ROS levels and the oxidized purine adduct, 8-oxo-G.…”

“…Since curcumin has been characterized as raising cellular levels of reactive oxygen species (ROS) [17,18], we measured ROS production using 2′,7′-dichlorofluorescein diacetate. Result showed no significant difference in DCF fluorescence in the matched sets of MMR-proficient/deficient cells (see Suppl.…”

“…Other studies documented that curcumin-induced apoptosis and cell-cycle arrest in melanoma cells was associated with downregulation of NFκB activation, decreased iNOS and DNA-PK catalytic subunit expression, upregulation of p53, p21(Waf1/Cip1), p27(Kip1) and Chk2 [14, 15]. Curcumin-mediated inhibition of NF-κB via the NIK/IKK signaling complex results in excessive generation of reactive oxygen species (ROS) which ultimately trigger apoptosis through activation of c-Abl>JNK signaling [16, 17]. In sum, available evidence indicates that curcumin targets multiple signaling pathways to induce cell-cycle arrest and/or cell death.…”

Role of c-Abl Kinase in DNA Mismatch Repair-dependent G2 Cell Cycle Checkpoint Arrest Responses

“…Others have demonstrated that c-Abl inhibition by Gleevec TM can protect cells from DNA-damaging agents, including H 2 O 2 , Ara-C, and curcumin (40). Collectively, these results suggest that caution should be taken in clinical protocols that combine STI571 (or other c-Abl/Src inhibitors) with chemotherapeutic agents that are modulated by MMR (e.g.…”

Anticancer and carcinogenic properties of curcumin: Considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent

“…This report also shows that curcumin sensitizes human cancer cells to chemotherapy and radiation through down-regulation of this oncogen [173] Induction of proteasome-mediated down-regulation of cyclin E and up-regulation of the CDK inhibitors p21 and p27 in several cancer cell lines; these effects may contribute to the antiproliferative effects of curcumin against various tumors [337] Inhibition of the Akt/mammalian target of rapamycin (mTOR)/p70S6K and the extracellular signal-regulated kinases 1/2 (ERK1/2) pathways. These effects resulted in the induction of authophagy (a response of cancer cells to various anticancer therapies, also designated as programmed cell death type II) and suppression of the growth of malignant gliomas [322] Inhibition of Akt and its key target Bad in B lymphoma via inhibition of spleen tyrosine kinase (Syk) [299] This report shows that c-Abl, a nonreceptor tyrosine kinase that regulates stress responses induced by oxidative agents such as ionizing radiation and H2O2, regulates curcumin-induced cell death through activation of c-Jun N-terminal kinase [338] Induction of an increase in the protein levels of the proapoptotic Bcl-2 family members Bax and Bak, which was essential for maximum apoptotic activity [339] Regulation of signal transducer and activator of transcription (STAT) [297,340,341] Inhibition of human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor (EGFR) through reduction of the activity of the transcription factor Egr-1 [249] Inhibition of constitutively activated targets of PI3'-kinase (AKT, FOXO and GSK3) in T-cell acute lymphoblastic leukemia cells, leading to the inhibition of proliferation and induction of caspase-dependent apoptosis [296] Down-regulation of the Notch-1 signaling pathway [289] [81] 3.6 g/day/7 days Low nM levels in the peripheral or portal circulation, not found in liver tissue [71] the generation of new blood vessels, is necessary for the formation of solid tumors; without vascular growth, the tumor mass is restricted to a tissue-diffusion distance of approximately 0.2 mm. Malignant tumors are known to activate angiogenesis, and several reports have shown that curcumin can inhibit angiogenesis in vivo.…”