title: Selective Akt inactivation and tumor necrosis actor-related apoptosis-inducing ligand sensitization of renal cancer cells by low concentrations of paclitaxel.
abstract: Recent studies demonstrated that the resistance of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) could be reversed by various chemotherapeutic agents. In the present study, we investigated the role of Akt in the apoptosis resistance to TRAIL and chemotherapeutic agents-induced TRAIL sensitization in human renal cell carcinoma cells. Apoptosis assays and Western blot analyses revealed that apoptosis resistance to TRAIL correlates well with the level of Akt phosphorylation at Ser 473 rather than protein expression levels of TRAIL receptors, DR4 and DR5. The apoptosis sensitivity to TRAIL in TRAIL-resistant SKRC-49 and TRAIL-sensitive Caki-1 cells was altered by modulation of Akt activity, which increased the protein expression of cellular FADD-like IL-1beta-converting enzyme-like inhibitory protein (cFLIP). Paclitaxel (5 and 100 nM) and cisplatin (10 microM) but not etoposide (1 and 10 microM) promoted TRAIL-induced apoptosis in SKRC-49 cells, which was not mediated by increased TRAIL receptor expression but by chemotherapeutic agents-induced Akt inactivation through ceramide formation derived from sphingomyelin hydrolysis. Of note, the low concentration (5 nM) of paclitaxel promoted ceramide formation and TRAIL-induced apoptosis predominantly in SKRC-49 cells but not in the normal renal proximal tubular epithelial cells. Our results may provide a novel therapeutic modality for selective killing of renal cell carcinoma with minimal toxicity on normal renal cells.
authors.affiliation: Department of Urology, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Asakuma
authors.forename: Makoto
authors.initials: M
authors.lastname: Sumitomo
authors.forename: Takako
authors.initials: T
authors.lastname: Asano
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Asano
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hayakawa
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000201:enzymology; D002352:Carrier Proteins / Q000096:biosynthesis; D002518:Ceramides / Q000096:biosynthesis; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D047908:Intracellular Signaling Peptides and Proteins; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000201:enzymology; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013109:Sphingomyelins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D002518:Ceramides; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D013109:Sphingomyelins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel; D002945:Cisplatin