title: Restoration of tumor suppressor p53 by differentially regulating pro- and anti-p53 networks in HPV-18-infected cervical cancer cells.
abstract: Abrogation of functional p53 is responsible for malignant cell transformation and maintenance of human papilloma virus (HPV)-infected cancer cells. Restoration of p53 has, therefore, been regarded as an important strategy for molecular intervention of HPV-associated malignancies. Here we report that differential regulation of pro- and anti-p53 setups not only upregulates p53 transcription but also stabilizes and activates p53 protein to ensure p53-induced apoptosis in HPV-18-infected cervical cancer. Functional restoration of p53 can be achieved by non-steroidal anti-inflammatory drug celecoxib via multiple molecular mechanisms: (i) inhibition of p53 degradation by suppressing viral oncoprotein E6 expression, (ii) promoting p53 transcription by downmodulating cycloxygenase-2 (Cox-2) and simultaneously retrieving p53 from Cox-2 association and (iii) activation of p53 via ataxia telangiectasia mutated-/p38 mitogen-activated protein kinase-mediated phosphorylations at serine-15/-46 residues. That restored p53 is functional has been confirmed by its ability of transactivating Bax and p53-upregulated modulator of apoptosis, which in turn switch on the apoptotic machinery in these cells. Studies undertaken in biopsy samples of cervical carcinoma further validated celecoxib effect. Our approaches involving gene manipulation and pharmacological interference finally highlight that celecoxib alters pro- and anti-p53 networks, not in isolation but in concert, to rejuvenate p53-dependent apoptotic program in HPV-infected cervical cancer cells.
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata, India.
authors.forename: B
authors.initials: B
authors.lastname: Saha
authors.forename: A
authors.initials: A
authors.lastname: Adhikary
authors.forename: P
authors.initials: P
authors.lastname: Ray
authors.forename: S
authors.initials: S
authors.lastname: Saha
authors.forename: S
authors.initials: S
authors.lastname: Chakraborty
authors.forename: S
authors.initials: S
authors.lastname: Mohanty
authors.forename: K
authors.initials: K
authors.lastname: Das
authors.forename: S
authors.initials: S
authors.lastname: Mukherjee
authors.forename: M
authors.initials: M
authors.lastname: Mazumdar
authors.forename: L
authors.initials: L
authors.lastname: Lahiri
authors.forename: D M S
authors.initials: DM
authors.lastname: Hossain
authors.forename: G
authors.initials: G
authors.lastname: Sa
authors.forename: T
authors.initials: T
authors.lastname: Das
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D000068579:Celecoxib; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D016158:Genes, p53; D052161:Human papillomavirus 18 / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000068579:Celecoxib