title: Caspase-mediated cleavage of beta-catenin precedes drug-induced apoptosis in resistant cancer cells.
abstract: A delicate balance between cell death and survival pathways maintains normal physiology, which is altered in many cancers, shifting the balance toward increased survival. Several studies have established a close connection between the Wnt/beta-catenin pathway and tumorigenesis, aberrant activation of which might contribute toward increased cancer cell growth and survival. Extensive research is underway to identify therapeutic agents that can induce apoptosis specifically in cancer cells with minimal collateral damage to normal cells. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis specifically in tumor cells, many cancer cells develop resistance, which can be overcome by combinatorial treatment with other agents: for example, peroxisome proliferator-activated receptor gamma (PPARgamma) ligands. To identify the molecular target mediating combinatorial drug-induced apoptosis, we focused on beta-catenin, a protein implicated in oncogenesis. Our results show that co-treatment of TRAIL-resistant cancer cells with TRAIL and the PPARgamma ligand troglitazone leads to a reduction of beta-catenin expression, coinciding with maximal apoptosis. Modulation of beta-catenin levels via ectopic overexpression or small interference RNA-mediated gene silencing modulates drug-induced apoptosis, indicating involvement of beta-catenin in regulating this pathway. More in-depth studies indicated a post-translational mechanism, independent of glycogen synthase kinase-3beta activity regulating beta-catenin expression following combinatorial drug treatment. Furthermore, TRAIL- and troglitazone-induced apoptosis was preceded by a cleavage of beta-catenin, which was complete in a fully apoptotic population, and was mediated by caspases-3 and -8. These results demonstrate beta-catenin as a promising new target of drug-induced apoptosis, which can be targeted to sensitize apoptosis-resistant cancer cells.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition Loyola University, Chicago, Maywood, Illinois 60153.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Senthivinayagam
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition Loyola University, Chicago, Maywood, Illinois 60153.
authors.forename: Prajna
authors.initials: P
authors.lastname: Mishra
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition Loyola University, Chicago, Maywood, Illinois 60153.
authors.forename: Suresh Kanna
authors.initials: SK
authors.lastname: Paramasivam
authors.affiliation: Department of Internal Medicine, The Texas A&M University System-Health Science Center, College of Medicine, Temple, Texas 76504.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Yallapragada
authors.affiliation: Division of Biochemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India 700032.
authors.forename: Malay
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Division of Hematology/Oncology, Scott & White Hospital, Temple, Texas 76504.
authors.forename: Lucas
authors.initials: L
authors.lastname: Wong
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Loyola University, Chicago, Maywood, Illinois 60153; Hines Veterans Affairs Medical Center, Hines, Illinois 60141.
authors.forename: Ajay
authors.initials: A
authors.lastname: Rana
authors.affiliation: Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition Loyola University, Chicago, Maywood, Illinois 60153; Department of Pharmacology and Experimental Therapeutics, Loyola University, Chicago, Maywood, Illinois 60153; Hines Veterans Affairs Medical Center, Hines, Illinois 60141. Electronic address: brana@lumc.edu.
authors.forename: Basabi
authors.initials: B
authors.lastname: Rana
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D009363:Neoplasm Proteins / Q000819:agonists / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D002839:Chromans; D009363:Neoplasm Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D045162:Thiazolidinediones; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D000077288:Troglitazone