TRAIL/Apo2L ligands induce apoptosis in malignant rhabdoid tumor cell lines.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a potent inducer of apoptosis in various cancer cells, whereas normal cells are not sensitive to TRAIL-mediated apoptosis. Four TRAIL/Apo2L receptors (DR4, DR5, DcR1, and DcR2) have been identified. DR4 and DR5 have a death domain, whereas DcR1 and DcR2 are called decoy receptors because of their incomplete or lack of a death domain. Malignant rhabdoid tumor (MRT) is an aggressive neoplasm showing a poor prognosis because of its resistance to chemotherapeutic agents. In this study, we examined whether TRAIL could induce apoptotic cell death in MRT cell lines. We found that although half of the MRT cell lines examined were sensitive to TRAIL/Apo2L, Western blot analysis revealed that the expression of DcR2 was low in TRAIL-sensitive MRT cells. We examined the effect of doxorubicin on the expression levels of TRAIL receptors and its enhancement on the susceptibility of MRT cell lines to TRAIL. Western blot and flow cytometric analyses revealed that doxorubicin significantly increased the expression of DR5, and somewhat up-regulated the expression of DR4 and DcR2. Moreover, doxorubicin, NF-kappaB inhibitor (SN50), and PI3-kinase/Akt inhibitor (wortmannin, LY294002) enhanced the susceptibility of MRT cell lines to TRAIL/Apo2L-induced apoptosis. These results suggest that TRAIL/Apo2L may provide the basis for clinical trials of TRAIL-based treatment to improve the outcome of MRT patients.
Yoshida
Shinobu
S
Department of Pediatrics, Shiga University of Medical Science, Tsukinowa-cho, Seta, Shiga 520-2192, Japan.
Narita
Tsutomu
T
Koshida
Shigeki
S
Ohta
Shigeru
S
Takeuchi
Yoshihiro
Y
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor / Q000502:physiology*; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000378:metabolism* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
D017304:Annexin A5; D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D004317:Doxorubicin; D004791:Enzyme Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; C505653:TNFSF10 protein, human