Acquired resistance to TRAIL-induced apoptosis in human ovarian cancer cells is conferred by increased turnover of mature caspase-3

Abstract

Little is known on how cancer cells can acquire resistance to tumor necrosis factor -related apoptosis-inducing ligand (TRAIL). In this study, we established TRAIL-resistant cells from the TRAIL-sensitive human ovarian carcinoma cell line OVCAR3 to evaluate the potential mechanisms of acquired resistance to TRAIL. The selected resistant cells were cross-resistant to Fas ligand but remained sensitive to drug-induced apoptosis. Expression of TRAIL receptors was not altered in TRAIL-resistant OVCAR3 cells. Cleavage of caspase-8 and caspase-3 occurred in both TRAILresistant and TRAIL-sensitive cells. However, mature caspase-3 fragments were not detected by immunoblot in TRAIL-resistant cells and caspase-3 activity was significantly inhibited in these cells. The addition of proteasome inhibitors significantly increased TRAIL-induced apoptosis in resistant cells and enhanced the accumulation of mature caspase-3 fragments. Pretreatment with cycloheximide showed that active caspase-3 fragments have a high turnover rate in OVCAR3 R350 cells. X-linked inhibitor of apoptosis down-regulation by RNA interference also increased the accumulation of cleaved caspase-3 intermediates and resensitized TRAIL-resistant cells. Our findings show that altered turnover of mature caspase-3 may lead to acquired TRAIL resistance in ovarian cancer cells. Proteasome and X-linked inhibitor of apoptosis inhibitors could have a role in clinical situations to potentiate the cytotoxic effects of TRAIL in resistant tumor cells. [Mol Cancer Ther 2006;5(3):509 -21]

Downregulation of active caspase 8 as a mechanism of acquired TRAIL resistance in mismatch repair-proficient colon carcinoma cell lines

“…1B). The ~30% surviving fraction is consistent with previous model of TRAIL resistance in cancer cell lines treated with TRAIL for several months (17,18).…”

3,3′-diindolylmethane potentiates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of gastric cancer cells

“…However, to the best of our knowledge, the present study is the first to demonstrate that DIM sensitizes TRAIL-induced cytotoxicity and apoptosis in gastric cancer cells. As the widespread application of TRAIL has been limited due to increasing drug resistance and cost (3,4), the results of the current study indicate that the use of low-cost DIM may enhance the clinical application of TRAIL-based therapy for various types of cancer in the future.…”

“…For example, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an agent that is preferentially cytotoxic to cancer cells over healthy cells (2). However, the effectiveness of TRAIL is significantly impeded by drug resistance, resulting in poor survival outcomes of patients with cancer (3,4). Emerging evidence provides support for the potential anticancer effect of bioactive products derived from cruciferous vegetables, such as brussel sprouts, broccoli, cabbage and cauliflower (5).…”

Antiapoptotic Proteins Bcl-2 and Bcl-X L Inhibit Clostridium difficile Toxin A-Induced Cell Death in Human Epithelial Cells

“…Human ovarian and colonic carcinoma cell lines were used to investigate TcdA-induced cell death. We have previously characterized the mechanisms of TRAIL-and drug-induced cell death in the ovarian carcinoma cell lines CaOV3 and OVCAR3 (8,(19)(20)(21). Efficient TRAIL-induced cell death in these cell lines requires interconnection between the cell surface death receptor and the mitochondrion-dependent apoptotic pathway and is highly dependent on caspase activation.…”