The Absence of NF-κB-Mediated Inhibition of c-Jun N-Terminal Kinase Activation Contributes to Tumor Necrosis Factor Alpha-Induced Apoptosis

Abstract

The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-α exerts its biological activities by activating multiple signaling pathways, including IκB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-κB, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-κB pathway, TNF-α is able to induce apoptosis in cells sensitive to it, such as human breast carcinoma MCF-7 and mouse fibroblast LM cells. The molecular mechanism underlying TNF-α-induced apoptosis is incompletely understood. Here we report that in TNF-α-sensitive cells activation of the IKK/NF-κB pathway fails to block TNF-α-induced apoptosis, although its inactivation still promotes TNF-α-induced apoptosis. Interestingly, TNF-α-induced apoptosis is suppressed by inhibition of the JNK pathway but promoted by its activation. Furthermore, activation of JNK by TNF-α was transient in TNF-α-insensitive cells but prolonged in sensitive cells. Conversion of JNK activation from prolonged to transient suppressed TNF-α-induced apoptosis. Thus, absence of NF-κB-mediated inhibition of JNK activation contributes to TNF-α-induced apoptosis.

Evidence for colorectal cancer cell specificity of aspirin effects on NFκB signalling and apoptosis

“…These results contrast with some previous reports of NSAID-induced growth inhibition and apoptosis in breast and endometrial cancer cells (Noguchi et al, 1995;Planchon et al, 1995;Han et al, 1998;Arango et al, 2001), but these differences are reconciled by considering that these studies used NSAIDs other than aspirin (Noguchi et al, 1995;Planchon et al, 1995;Han et al, 1998), while others only observed apoptosis after long exposures (48 -96 h) to high concentrations of salicylate out with the therapeutic range (Sotiriou et al, 1999;Arango et al, 2001). The non-CRC cell lines are susceptible to other apoptosis-inducing agents and NFkB activators such as staurosporine and TNFa, respectively, indicating that these cell lines are not generally resistant to apoptosis or NFkB modulation (Mooney et al, 2002;Tang et al, 2002). The observation that aspirin decreased cell viability in one of the three breast cancer cell lines (T47D) is in keeping with epidemiological data that suggest a lesser protective effect of NSAIDs against breast cancer.…”

Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase

“…Several studies have shown that a persistent activation of JNK, which can be attained by inhibiting NF-kB activity, leads to cell death (De Smaele et al, 2001;Javelaud and Besancon, 2001;Tang et al, 2001Tang et al, , 2002. In contrast, transient JNK activation coupled with NF-kB activation leads to an antiapoptotic response through overexpression of the antiapoptotic cIAP-2 protein (Lamb et al, 2003).…”

c-Jun N-terminal Kinase Contributes to Apoptotic Synergy Induced by Tumor Necrosis Factor-related Apoptosis-inducing Ligand plus DNA Damage in Chemoresistant, p53 Inactive Mesothelioma Cells

“…If indeed, TRAIL activated MKK7 and etoposide activated MKK4, the combination would activate JNK better than each alone and perhaps lead to apoptotic synergy. In addition, an increased duration of JNK signaling may be important for JNK-induced apoptosis (32); such an increased duration can result if one stimulus blocks an inhibition, such as by NF-B, to the alternate stimulus (52). Apoptotic synergy could further be explained by actions distal to JNK as, for example, if JNK signals sensitized the mitochondria to respond to TRAIL-induced signals via caspase 8-mediated cleavage of the Bcl-2 homology molecule, BID.…”