Wogonin induces apoptosis by suppressing E6 and E7 expressions and activating intrinsic signaling pathways in HPV-16 cervical cancer cells

Abstract

Wogonin is a flavonoid compound extracted from Scutellaria baicalensis and is well known as a benzodiazepine receptor ligand with anxiolytic effects. Many recent studies have demonstrated that wogonin modulates angiogenesis, proliferation, invasion, and tumor progress in various cancer tissues. We further explored the mechanism of action of wogonin on cervical cancer cells that contain or lack human papillomavirus (HPV) DNA. Wogonin was cytotoxic to HPV 16 (+) cervical cancer cells, SiHa and CaSki, but not to HPV-negative cells. We demonstrated that wogonin induced apoptosis by suppressing the expressions of the E6 and E7 viral oncogenes in HPV-infected cervical cancer CaSki and SiHa cells. The modulation of p53 and protein retinoblastoma (pRb) were also triggered by the suppression of E6 and E7 expressions. However, p53 was not altered in HPV-negative cervical cancer C33A cells. Moreover, wogonin modulated the mitochondrial membrane potential and the expression of pro- and anti-apoptotic factors such as Bax and Bcl-2. Wogonin also provoked the cleavage of caspase-3, caspase-9, and poly ADP ribose polymerase. After transfection of siRNAs to target E6 and E7, additional restoration of p53 and pRb was not induced, but processing of caspases and PARP was increased compared with wogonin treatment alone. Together, our findings demonstrated that wogonin effectively promotes apoptosis by downregulating E6 and E7 expressions and promoting intrinsic apoptosis in human cervical cancer cells.

Korean Byungkyul - Citrus platymamma Hort.et Tanaka flavonoids induces cell cycle arrest and apoptosis, regulating MMP protein expression in Hep3B hepatocellular carcinoma cells

“…In intrinsic pathway or mitochondrial pathway, the balance between Bcl-2 family members such as Bcl-xL and Bax is important while in extrinsic apoptosis pathway Fas and FasL are the key inducers. In both the pathways cleavage of caspases and PARP plays a crucial role (20,21). Fig.…”

Ethylacetate extract from Tetrastigma hemsleyanum induces apoptosis via the mitochondrial caspase-dependent intrinsic pathway in HepG2 cells

“…EET treatment resulted in mitochondrial membrane potential collapse and the release of cytochrome c Mitochondrial dysfunction has been reported to play a vital role in intrinsic apoptosis processes, which is characterized by the collapse of transmembrane potential [12]. In view of the increase in levels of activated caspase-3 and caspase-9 that was observed in HepG 2 cells exposed to EET, we then evaluated whether treatment with EET induced a loss in mitochondria transmembrane potential (⊿ψm) and the release of cytochrome c from mitochondria as proof of mitochondriamediated apoptosis.…”

Human Papillomavirus E6 and E7: The Cervical Cancer Hallmarks and Targets for Therapy

“…E6 and E7 oncogenes have been found to induce the epithelialto-mesenchymal transition (EMT), a process required for the tumor cells to invade into the bloodstream and metastasize at other place in the body. Using the epithelial MDCK cell line as an in vitro model, the study by Kim et al (2013) showed that ectopic expression of E6/E7 can induce cobblestone-shaped epithelial cell formation from spindle-shaped mesenchymal cells. Moreover, they also showed that E6 and E7 could activate the EMT-inducing transcriptional factors such as Slug, Twist, ZEB1, and ZEB2 followed by an increase in the migratory and invasive potentials of the cells.…”