title: Modulation of p73 isoforms expression induces anti-proliferative and pro-apoptotic activity in mantle cell lymphoma independent of p53 status.
abstract: Mantle cell lymphoma (MCL) is characterized by a clinically aggressive course with frequent relapse and poor survival. The p53 pathway is frequently dysregulated and p53 status predicts clinical outcome. In this report, we investigated whether modulation of p73 isoforms by diclofenac inhibits cell growth, induces apoptosis and/or cell cycle arrest in MCL relative to p53 status. Wild-type p53 [Granta-519 and JVM-2], mutant p53 [Jeko-1 and Mino-1] expressing cells, therapy resistant cell lines, and primary human cells isolated from MCL patients were used. Overexpression of pro-apoptotic TAp73 enhanced MCL cell apoptosis. Diclofenac induced a concentration- and duration-dependent increase in TAp73, cell cycle arrest, cell death, and inhibited MCL cell growth independent of p53 status. Diclofenac treatment was associated with increased activity of caspases 3, 7, and 8 and induction of p53 transcriptional target genes. These studies demonstrate the potential for diclofenac as novel therapeutic agent in MCL independent of p53 status.
authors.affiliation: a Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , NE , USA.
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Hassan
authors.affiliation: a Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , NE , USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Varney
authors.affiliation: b Department of Genetics, Cell Biology and Anatomy , University of Nebraska Medical Center , Omaha , NE , USA.
authors.forename: Nagendra K
authors.initials: NK
authors.lastname: Chaturvedi
authors.affiliation: b Department of Genetics, Cell Biology and Anatomy , University of Nebraska Medical Center , Omaha , NE , USA.
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
authors.affiliation: c Department of Pathology , City of Hope Medical Center , Duarte , CA , USA.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.affiliation: a Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , NE , USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: a Department of Pathology and Microbiology , University of Nebraska Medical Center , Omaha , NE , USA.|d Human Genetics Laboratories , Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center , Omaha , NE , USA.
authors.forename: Bhavana J
authors.initials: BJ
authors.lastname: Dave
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D004008:Diclofenac / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms; D000072160:Tumor Protein p73 / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D004008:Diclofenac; D020169:Caspases
keywords: Apoptosis; cell cycle; diclofenac; mantle cell lymphoma; p73 isoforms