title: Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-gingerol in cervical cancer cells.
abstract: Human papilloma virus (HPV) expressing E6 and E7 oncoproteins, is known to inactivate the tumor suppressor p53 through proteasomal degradation in cervical cancers. Therefore, use of small molecules for inhibition of proteasome function and induction of p53 reactivation is a promising strategy for induction of apoptosis in cervical cancer cells. The polyphenolic alkanone, 6-Gingerol (6G), present in the pungent extracts of ginger (Zingiber officinale Roscoe) has shown potent anti-tumorigenic and pro-apoptotic activities against a variety of cancers. In this study we explored the molecular mechanism of action of 6G in human cervical cancer cells in vitro and in vivo. 6G potently inhibited proliferation of the HPV positive cervical cancer cells. 6G was found to: (i) inhibit the chymotrypsin activity of proteasomes, (ii) induce reactivation of p53, (iii) increase levels of p21, (iv) induce DNA damage and G2/M cell cycle arrest, (v) alter expression levels of p53-associated apoptotic markers like, cleaved caspase-3 and PARP, and (vi) potentiate the cytotoxicity of cisplatin. 6G treatment induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in HeLa xenograft tumor cells in vivo. The 6G treatment was devoid of toxic effects as it did not affect body weights, hematological and osteogenic parameters. Taken together, our data underscores the therapeutic and chemosensitizing effects of 6G in the management and treatment of cervical cancer.
authors.affiliation: Cell Death Research Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Namrata
authors.initials: N
authors.lastname: Rastogi
authors.affiliation: Department of Radiotherapy, King George Medical University, Lucknow, India.
authors.forename: Shivali
authors.initials: S
authors.lastname: Duggal
authors.affiliation: Department of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
authors.forename: Shailendra Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Cell Death Research Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Konica
authors.initials: K
authors.lastname: Porwal
authors.affiliation: Department of Radiotherapy, King George Medical University, Lucknow, India.
authors.forename: Vikas Kumar
authors.initials: VK
authors.lastname: Srivastava
authors.affiliation: Medicinal Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.affiliation: Department of Radiotherapy, King George Medical University, Lucknow, India.
authors.forename: M L B
authors.initials: ML
authors.lastname: Bhatt
authors.affiliation: Cell Death Research Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Durga Prasad
authors.initials: DP
authors.lastname: Mishra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002396:Catechols / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005233:Fatty Alcohols / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D062105:Molecular Docking Simulation; D030361:Papillomavirus Infections / Q000150:complications; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002396:Catechols; D005233:Fatty Alcohols; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C007845:gingerol; D046988:Proteasome Endopeptidase Complex
keywords: 6-gingerol; Chromosome Section; HPV; cervical cancer; p53 reactivation; proteasome