title: Galectin-3 inhibits tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by activating Akt in human bladder carcinoma cells.
abstract: The antiapoptotic molecule galectin-3 was previously shown to regulate CD95, a member of the tumor necrosis factor (TNF) family of proteins in the apoptotic signaling pathway. Here, we question the generality of the phenomenon by studying a different member of this family of proteins [e.g., TNF-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in a wide variety of cancer cells]. Overexpression of galectin-3 in J82 human bladder carcinoma cells rendered them resistant to TRAIL-induced apoptosis, whereas phosphatidylinositol 3-kinase (PI3K) inhibitors (wortmannin and LY-294002) blocked the galectin-3 protecting effect. Because Akt is a major downstream PI3K target reported to play a role in TRAIL-induced apoptosis, we questioned the possible relationship between galectin-3 and Akt. Parental J82 and the control vector-transfected J82 cells (barely detectable galectin-3) exhibit low level of constitutively active Akt, resulting in sensitivity to TRAIL. On the other hand, J82 cells overexpressing galectin-3 cells expressed a high level of constitutively active Akt and were resistant to TRAIL. Moreover, the blockage of TRAIL-induced apoptosis in J82 cells seemed to be mediated by Akt through the inhibition of BID cleavage. These results suggest that galectin-3 involves Akt as a modulator molecule in protecting bladder carcinoma cells from TRAIL-induced apoptosis.
authors.affiliation: Tumor Progression and Metastasis, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Natsuo
authors.initials: N
authors.lastname: Oka
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakahara
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Takenaka
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Fukumori
authors.forename: Victor
authors.initials: V
authors.lastname: Hogan
authors.forename: Hiro-Omi
authors.initials: HO
authors.lastname: Kanayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Yanagawa
authors.forename: Avraham
authors.initials: A
authors.lastname: Raz
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D037502:Galectin 3 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D037502:Galectin 3; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; C505653:TNFSF10 protein, human; C494918:AKT1 protein, human; C505407:CASP3 protein, human; C506433:CASP9 protein, human