Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-Gingerol in cervical cancer cells

// Namrata Rastogi 1 , Shivali Duggal 2 , Shailendra Kumar Singh 3 , Konica Porwal 1 , Vikas Kumar Srivastava 2 , Rakesh Maurya 4 , Madan  L.B. Bhatt 2 and Durga Prasad Mishra 1 1 Cell Death Research Laboratory, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India 2 Department of Radiotherapy, King George Medical University, Lucknow, India 3 Department of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan 4 Medicinal Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, India Correspondence to: Durga Prasad Mishra, email: // Keywords : proteasome, p53 reactivation, cervical cancer, HPV, 6-Gingerol, Chromosome Section Received : June 12, 2015 Accepted : November 17, 2015 Published : November 25, 2015 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.