Lack of p38 MAP Kinase Activation in TRAIL-Resistant Cells is Not Related to the Resistance to TRAIL-Mediated Cell Death

Abstract

Activation of MAP kinases is involved in various cellular processes, including immunoregulation, inflammation, cell growth, cell differentiation, and cell death. To investigate the role of p38 MAP kinase activation in the signaling pathway of TRAIL-mediated apoptosis, we compared TRAIL-mediated MAP kinase activation in TRAIL-susceptible human colon cancer cell line DLD1 and TRAIL-resistant DLD1/TRAIL-R cells. TRAIL-mediated activation of ERK occurred in both cell lines. In contrast, both DLD1 and DLD1/TRAIL-R cells showed no obvious JNK activation after treatment with TRAIL. Interestingly, TRAIL-mediated activation of p38 MAP kinases was observed in DLD1 cells but not in DLD1/TRAIL-R cells. However, activation of p38 MAP kinases was observed in both DLD1 and DLD1/TRAIL-R cells after treatment with anisomycin. Furthermore, inhibiting activated p38 MAP kinases with known inhibitors or with an adenovector expressing dominant negative p38α did not block TRAIL-mediated cell death in DLD1 cells. Moreover, activation of p38 MAP kinases by adenovectors expressing constitutive MKK3 or MKK6 (Ad/MKK3bE or Ad/MKK6bE) did not induce cell death in either DLD1 or DLD1/TRAIL-R cell lines. Our results suggest that activation of p38 MAP kinases does not play a major role in TRAIL-mediated apoptosis in DLD1 cells and that lack of TRAIL-mediated p38 MAP kinase activation may not be the mechanism of TRAIL-resistance in DLD1/TRAIL-R cells. INTRODUCTIONThe tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily. Like the other two members of this superfamily TNF-α and Fas ligand, TRAIL has strong antitumor activity both in vitro and in vivo in a wide range of cancer cell types. 1 Unlike TNF-α and Fas ligand, however, TRAIL exhibits minimal cytotoxity to most of normal cells and tissues and, therefore, shows potential of its becoming a new therapeutic agent for cancer treatment. [2][3][4] For most cell types, TRAIL induces cell death through apoptosis. Although the detailed mechanisms of the signaling pathway of TRAIL-induced apoptosis are still unclear, some important components and steps in the signaling pathway have already been elucidated. The interaction of TRAIL and its two death receptors, DR4 (TRAIL-R1) and/or DR5 (TRAIL-R2), is the initial step of TRAIL-induced apoptosis. 5,6 The binding of TRAIL to its receptors leads to trimerization and activation of the death receptors. The activated death receptors recruit and activate an adaptor protein called FADD (Fas-associated death domain), which in turn recruits and activates caspase-8, leading to the formation of the death-inducing signaling complex (DISC). 7,8 Once caspase-8 is activated, it can lead to apoptosis either by activating effector caspase-3 and -7, which in turn act on final death substrates, 8 or by activating Bid, which induces the accumulation of Bax in mitochondria, the release of cytochrome c from mitochondria, the activation of caspases-9, -3, and -7, and finally programmed cell death. 9,...

Eliminating Established Tumor in nu/nu Nude Mice by a Tumor Necrosis Factor-α-Related Apoptosis-Inducing Ligand–Armed Oncolytic Adenovirus

“…The significance of the difference between Ad/TRAIL-E1 and Ad/ GFP-E1 in generating progeny is not yet clear. However, it is known that in addition to inducing apoptosis, TRAIL induces activation of various other signaling pathways, including Akt (32, 33), nuclear factor-nB (32,34), and mitogen-activated protein kinases, such as JNK (34,35), p38 (36), and extracellular signal-regulated kinase (33,36). Many of those signaling pathways are required for or supportive of viral replication (37 -40), yet the roles of these pathways in the replication of oncolytic TRAIL adenovirus are not known.…”

Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy

“…42 However, in some other tumor cells such as the human colorectal cancer cell line DLD1, p38 did not play a major role in TRAILmediated apoptosis. 43 For example, although p38 was activated in TRAIL-sensitive DLD1 cells but not in TRAIL-resistant DLD1 cells, p38 inhibition did not block TRAIL-mediated cell death. Therefore, the role of p38 in TRAIL-induced apoptosis might also be cell-type dependent.…”

Mechanisms of resistance to TRAIL-induced apoptosis in cancer

“…Finally, we have noted p38 MAP kinase activation in colon cancer DLD1 cell line upon TRAIL treatment; however, inhibition of that activation was not related to development of TRAIL resistance in that cell line. 88 The functions of MAP kinases in TRAIL-induced apoptosis are further complicated by their involvement in cytokine secretion, particularly TNF-a, IL-1b, and IL-6. 89 …”