In this respect, a previous report showed that TNF-�� can activate c-Abl and upregulate apoptotic p73 function via a caspase-dependent elimination of retinoblastoma protein, and thus unleashing the nuclear apoptotic effector, c-Abl [8]. Currently the molecular events linking caspase to non-cleaved c-Abl activation following TRAIL stimulation remains unknown, and despite further investigation is required. In contrast to reduced TRAIL sensitivity in colon cancer cells, STI571 did not change the susceptibility of PC3 and LNCaP cells to TRAIL. We ruled out such cell type-specific effects of STI571 being related to c-Abl protein expression. Similar expression levels of c-Abl were observed in HCT116, SW480, PC3, and LNCaP cells (data not shown).

Instead, we suggest that the antitumor activity of TRAIL in colon and prostate cancers might involve distinctive regulation and complex apoptotic pathways. In prostate cancers, neither p38 nor JNK activation by TRAIL is involved in cell death, while STI571 can still slightly inhibit TRAIL-induced JNK activation in prostate cancers. Moreover, TRAIL-mediated c-Abl cleavage displayed the same pattern in HCT116 and LNCaP cells. Therefore, these results further support the notion that the cell type-specific effect of STI571 on antitumor activity of TRAIL is dependent on the roles of p38 and JNK in cell death per se. Conclusions We demonstrate a novel mediator role of p73 in activating the stress kinases, p38 and JNK, in the apoptotic pathway of TRAIL (Figure (Figure7).7).

This action is initiated by caspase-dependent c-Abl activation, and is a key mechanism contributing to death receptor-mediated cell apoptosis in colon cancer, but not prostate cancer cells. Through inhibition of the c-Abl-mediated apoptotic p73 signaling, STI571 reduces the antitumor activity of TRAIL. In this sense, this study is not in favor of the cocktail therapy of STI571 and TRAIL in human colon cancers, and also highlights the cancer-specific effect of stress kinases on the antitumor activities of TRAIL. Figure 7 Signaling pathway for the cytoprotective effect of STI571 in TRAIL-treated colon cancer cells. In addition to induce classical apoptotic cascade elicited by caspases, TRAIL-induced apoptosis in colon cancer cells requires p38 and JNK activation. We propose …

Abbreviations CML: Chronic myelogenous leukemia; DR: Death receptor; FADD: Fas-associated protein with death domain; FasL: Fas ligand; JNK: c-Jun Anacetrapib NH2-terminal kinase; MAPK: Mitogen-activated protein kinase; MEKK: Mitogen-activated protein kinase kinase; MTT: 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide; PI: Propidium iodide; RB: Retinoblastoma; RIP: Receptor-interacting protein; TNF-��: Tumor necrotic factor-��; TRAF2: TNF receptor-associated factor 2; TRAIL: TNF-related apoptosis-inducing ligand; zVAD: z-Val-Ala-Asp-fluromethylketone. Competing interests The authors declare that they have no competing interests.