Abstract
TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, selectively induce apoptosis in various transformed cell lines but not in almost-normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2 and 2 decoy receptors, TRAIL-R3 and TRAIL-R4. However, the determining factors of the sensitivity to TRAIL-induced apoptosis are not clearly understood. Herein, we investigated the expression of TRAIL-R, c-FLIP, FADD-like interleukin-1beta-converting enzyme inhibitory protein, and TRAIL-induced apoptosis in human hepatocellular carcinoma (HCC) cell lines. Seven of ten HCC cell lines showed resistance to TRAIL-induced apoptosis and five of seven TRAIL-resistant cell lines became sensitive to TRAIL by co-treatment with cycloheximide. In HCC cell lines, their TRAIL resistance did not correlate with the basal expression level of TRAIL receptors or c-FLIP, however, in human tissues, TRAIL-R1 and TRAIL-R2 expressions were notably decreased compared to normal counterpart. Cisplatin showed synergistic effect on TRAIL-induced apoptosis in most HCC cell lines regardless of their p53 status and TRAIL-R1 was induced by cisplatin treatment in certain cell lines. Inhibition of nuclear factor K B (NF-kappaB) by SN50, a peptide inhibitor of NF-KB activity, had no effect on TRAIL-induced apoptosis in HCC cells. These results suggest that (a) the majority of human HCC cell lines are resistant to TRAIL-induced apoptosis and cycloheximide-sensitive short-lived antiapoptotic molecule(s) is responsible for this resistance, (b) the expression of TRAIL-R1 and TRAIL-R2 is reduced in HCC tissues, and the increased expression of TRAIL-R1 may be a mechanism of cisplatininduced sensitization to TRAIL-induced apoptosis in some HCC cells, and (c) the activation of NF-kappaB may not be involved in the TRAIL resistance of HCC cells
Highlights
TNF-related apoptosis-inducing ligand (TRAIL) is one of the apoptosis-inducing molecules belonging to the tumor necrosis factor (TNF) family (Wiley et al, 1995; Pitti et al, 1996)
hepatocellular carcinoma (HCC) cell lines treated with various combinations of TRAIL and cycloheximide for 24 h was assessed for cell survival
Cisplatin showed synergistic effect on TRAIL-induced apoptosis regardless of p53 status of HCC cell lines: Hep 3B is deficient of p53 and PLC/PRF/5, SNU-182, SNU-354, SNU-368 and SNU-449 do not express wild type p53 (Kang et al, 1996; Jia et al, 1997)
Summary
TNF-related apoptosis-inducing ligand (TRAIL) is one of the apoptosis-inducing molecules belonging to the tumor necrosis factor (TNF) family (Wiley et al, 1995; Pitti et al, 1996). TRAIL-R1 (DR4) and TRAIL-R2 (DR5) are typical death receptors, and belong to the death receptor family containing a death domain in their cytoplasmic tails (Pan et al, 1997a; Pan et al, 1997b; Screaton et al, 1997; Sheridan et al, 1997; Walczak et al, 1997). TRAIL-R3 (DcR1; TRID) and TRAIL-R4 (DcR2) are decoy receptors that have no or short cytoplasmic tail respectively, which lack a death domain (Degli-Esposti et al, 1997a; Degli-Esposti et al, 1997b; Pan et al, 1997a; Sheridan et al, 1997; Mongkolsapaya et al, 1998; Pan et al, 1998). Osteoprotegerin, a soluble receptor for TNF-related activation-induced cytokine (TRANCE), binds to TRAIL (Emery et al, 1998), and may act as a third decoy receptor
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