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.

Protective and therapeutic potential of ginger (Zingiber officinale) extract and [6]‐gingerol in cancer: A comprehensive review

“…Research findings indicated that restoration of the p53 function is critical for effective therapeutic targeting and management of cervical cancer (Horner, Defilippis, Manuelidis, & Dimaio, ). Rastogi et al, reported that [6]‐gingerol inhibits the proteasome and induced p53 reactivation and apoptotic cell death in cervical cancer cells. [6]‐Gingerol additionally potentiated the cytotoxic effects of cisplatin, which is a traditional chemotherapeutic agent.…”

“…In addition, [6]‐gingerol increased ROS production in cervical cancer cells. Generation of [6]‐gingerol‐induced intracellular ROS leads to apoptotic cell death, DNA damage, and p53/p21‐mediated G2/M cell cycle arrest (Rastogi et al, ). Furthermore, animals treated with [6]‐gingerol (2.5 and 5.0 mg/kg body weight) for 6 weeks showed a significant reduction in tumor volume (about 65%).…”

“…Expression of cell cycle regulators and other apoptotic markers were also observed according to in vitro studies. Potent antiproliferative effect of [6]‐gingerol in vivo is mediated by proteasomal inhibition and reactivation with p53, leading to inhibition of proliferation and induction of apoptotic cell death (Rastogi et al, ). [6]‐Gingerol was found to reduce the viability of HeLa (human cervical carcinoma) cells as shown by morphological changes in cells.…”

“…In addition, [6]-gingerol increased ROS production in cervical cancer cells. Generation of [6]-gingerol-induced intracellular ROS leads to apoptotic cell death, DNA damage, and p53/p21-mediated G2/M cell cycle arrest (Rastogi et al, 2015). Furthermore, animals treated with…”

[6]‐Gingerol enhances the cisplatin sensitivity of gastric cancer cells through inhibition of proliferation and invasion via PI3K/AKT signaling pathway

“…In recent years, [6]‐gingerol also has been found in numerous studies to exert anticancer activities in various cancers. For example, [6]‐gingerol has been reported to inhibit cell growth and induce apoptosis in cervical cancer cells (Rastogi et al, ). [6]‐Gingerol has also been found to inhibit cell invasion of human hepatocarcinoma cells (Weng, Chou, Ho, & Yen, ).…”