Regulation of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells.
Title | Regulation of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in thyroid carcinoma cells. |
Publication Type | Journal Article |
Year of Publication | 2002 |
Authors | Poulaki, V., Mitsiades C. S., Kotoula V., Tseleni-Balafouta S., Ashkenazi A., Koutras D. A., & Mitsiades N. |
Journal | Am J Pathol |
Volume | 161 |
Issue | 2 |
Pagination | 643-54 |
Date Published | 2002 Aug |
ISSN | 0002-9440 |
Keywords | Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Carrier Proteins, CASP8 and FADD-Like Apoptosis Regulating Protein, Flow Cytometry, Humans, Insulin-Like Growth Factor I, Intracellular Signaling Peptides and Proteins, Ligands, Membrane Glycoproteins, Signal Transduction, Thyroid Neoplasms, TNF-Related Apoptosis-Inducing Ligand, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha |
Abstract | Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/Apo2 ligand selectively kills neoplastic cells, including thyroid carcinoma cells (Mitsiades et al: Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res 2000, 60:4122-41299). We investigated the mechanisms regulating Apo2L/TRAIL-induced apoptosis in thyroid carcinoma cells, as well as the impact of insulin-like growth factor (IGF)-1, interferon-gamma, and TNF-alpha. We found that the emergence of resistance to Apo2L/TRAIL, after prolonged incubation with this cytokine, was associated with increased levels of FLICE inhibitory protein (FLIP), and was overcome by cycloheximide and bisindolylmaleimide, that specifically down-regulated FLIP expression, as well as by transfection of a FLIP anti-sense oligonucleotide. IGF-1 activated Akt; up-regulated the caspase inhibitors FLIP, cIAP-2, XIAP, and survivin; and attenuated Apo2L/TRAIL-induced apoptosis. This effect was inhibited by the IGF-1 receptor neutralizing antibody aIR3, the PI-3K inhibitor wortmannin, and the heat shock protein-90 chaperone inhibitor geldanamycin. Transfection of constitutively active Akt protected from TRAIL. Conversely, interferon-gamma and TNF-alpha had a sensitizing effect. We conclude that FLIP may negatively regulate Apo2L/TRAIL-induced apoptosis in thyroid carcinomas. Microenvironmental paracrine survival factors, such as IGF-1, up-regulate caspase inhibitors, including FLIP, and protect from Apo2L/TRAIL in a PI-3K/Akt-dependent manner. T helper-1 cytokines and compounds that selectively abrogate the IGF-1 signaling pathway may be helpful adjunct agents in Apo2L/TRAIL-based anti-cancer therapeutic regimens. |
DOI | 10.1016/S0002-9440(10)64220-4 |
Alternate Journal | Am J Pathol |
PubMed ID | 12163389 |
PubMed Central ID | PMC1850734 |