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

2013 ◽  
Vol 29 (4) ◽  
pp. 259-272 ◽  
Author(s):  
Man Sub Kim ◽  
Yesol Bak ◽  
Yun Sun Park ◽  
Dong Hun Lee ◽  
Jung Hee Kim ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Hpv 16 ◽  
Cervical Cancer Cells ◽  
E6 And E7

scholarly journals Hsps responsible for apoptosis induction failure in cervical cancer cells upon osthole and tamoxifen treatment

2019 ◽  
Vol 73 ◽  
pp. 563-571
Author(s):  
Joanna Jakubowicz-Gil ◽  
Roman Paduch ◽  
Krystyna Skalicka-Woźniak ◽  
Joanna Sumorek-Wiadro ◽  
Adrian Zając ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Cancer Cells ◽  
Cell Lines ◽  
Tamoxifen Treatment ◽  
Hpv 16 ◽  
Cervical Cancer Cells ◽  
Shock Proteins ◽  
Human Cervical Cancer

Aim: The aim of the present study was to investigate the efficacy of osthole (7-metoxy-8-isopenthenocoumarin) alone and combined with tamoxifen (TAM) in the elimination of human cervical cancer cells via programmed death. The involvement of heat shock proteins, i.e. well-known molecular chaperones, will be investigated. Material/Methods: Three human cervical cancer cell lines, infected with human papilloma virus (HPV), i.e. HeLa (HPV 18), SiHa (HPV 16), and CaSki (HPV 16 and 18), were used in the experiments. After osthole and TAM treatment, cells stained with fluorochromes were analyzed microscopically according to apoptotic, autophagic, and necrotic morphology. Hsp27, Hsp72, and Hsp90 levels were analyzed by immunoblotting. Transfection with specific siRNA was used for blocking of Hsp expression. Results: In the HeLa, CaSki, and SiHa cell lines, osthole and TAM applied alone had no significant effect on cell death induction. This was correlated with an overexpression of heat shock proteins 27, 72, and 90. In the case of a combination of both drugs, the level of apoptosis was elevated only in SiHa cells. Preincubation with osthole followed by TAM addition as well as simultaneous incubation with both drugs was the most effective. This was correlated with the inhibition of Hsp27, Hsp72, and Hsp90 expression. Blocking of Hsp expression with specific siRNA increased the sensitivity of the studied cell lines to the induction of apoptosis, but not to autophagy or necrosis. Conclusions: Our results indicated that the elimination of heat shock proteins from cervical cancer cells sensitized them to initiation of apoptosis after osthole and tamoxifen treatment.

Abstract 199: HPV-16 E6 silencing of p16INK4a in human cervical cancer cells

2010 ◽  
Author(s):  
Chi Lam Au Yeung ◽  
Tsun Yee Tsang ◽  
Ngai Na Co ◽  
Pak Lun Yau ◽  
Tim Tak Kwok
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Hpv 16 ◽  
Cervical Cancer Cells ◽  
Human Cervical Cancer Cells ◽  
Human Cervical Cancer

scholarly journals Interferon-β Induced microRNA-129-5p Down-Regulates HPV-18 E6 and E7 Viral Gene Expression by Targeting SP1 in Cervical Cancer Cells

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e81366 ◽  
Author(s):  
Jiarong Zhang ◽  
Shuangdi Li ◽  
Qin Yan ◽  
Xiaoyue Chen ◽  
Yixia Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Cancer Cells ◽  
Viral Gene Expression ◽  
Viral Gene ◽  
Interferon Β ◽  
Cervical Cancer Cells ◽  
E6 And E7 ◽  
Hpv 18

scholarly journals Endogenous Human Papillomavirus E6 and E7 Proteins Differentially Regulate Proliferation, Senescence, and Apoptosis in HeLa Cervical Carcinoma Cells

2003 ◽  
Vol 77 (2) ◽  
pp. 1551-1563 ◽  
Author(s):  
Rosa Anna DeFilippis ◽  
Edward C. Goodwin ◽  
Lingling Wu ◽  
Daniel DiMaio
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cancer Cells ◽  
Cervical Carcinoma ◽  
Carcinoma Cells ◽  
Rb Pathway ◽  
Cervical Cancer Cells ◽  
E6 And E7 ◽  
E7 Proteins ◽  
E6 Protein

ABSTRACT Cervical cancer cells express high-risk human papillomavirus (HPV) E6 and E7 proteins, and repression of HPV gene expression causes the cells to cease proliferation and undergo senescence. However, it is not known whether both HPV proteins are required to maintain the proliferative state of cervical cancer cells, or whether mutations that accumulate during carcinogenesis eliminate the need for one or the other of them. To address these questions, we used the bovine papillomavirus E2 protein to repress the expression of either the E6 protein or the E7 protein encoded by integrated HPV18 DNA in HeLa cervical carcinoma cells. Repression of the E7 protein activated the Rb pathway but not the p53 pathway and triggered senescence, whereas repression of the E6 protein activated the p53 pathway but not the Rb pathway and triggered both senescence and apoptosis. Telomerase activity, cyclin-dependent kinase activity, and expression of c-myc were markedly inhibited by repression of either E6 or E7. These results demonstrate that continuous expression of both the E6 and the E7 protein is required for optimal proliferation of cervical carcinoma cells and that the two viral proteins exert distinct effects on cell survival and proliferation. Therefore, strategies that inhibit the expression or activity of either viral protein are likely to inhibit the growth of HPV-associated cancers.

scholarly journals Utilization of a cell-penetrating peptide-adaptor for delivery of HPV protein E2 into cervical cancer cells to arrest cell growth and promote cell death

2020 ◽  
Author(s):  
Julia C. LeCher ◽  
Hope L. Didier ◽  
Robert L. Dickson ◽  
Lauren R. Slaughter ◽  
Juana C. Bejarano ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Penetrating Peptides ◽  
Viral Integration ◽  
E2 Protein ◽  
Cell Penetrating ◽  
Cervical Cancer Cells ◽  
E6 And E7

AbstractCervical cancer is the second leading cause of cancer deaths in women worldwide. Human papillomavirus (HPV) is the causative agent of nearly all forms of cervical cancer, which arises upon viral integration into the host genome and concurrent loss of regulatory gene E2. E2 protein regulates viral oncoproteins E6 and E7. Loss of E2 upon viral integration results in unregulated expression and activity of E6 and E7, which promotes carcinogenesis. Previous studies using gene-based delivery show that reintroduction of E2 into cervical cancer cell lines can reduce proliferative capacity and promote apoptosis. However, owing in part to limitations on transfection in vivo, E2 reintroduction has yet to achieve therapeutic usefulness. A promising new approach is protein-based delivery systems utilizing cell-penetrating peptides (CPPs). CPPs readily traverse the plasma membrane and are able to carry with them biomolecular ‘cargos’ to which they are attached. Though more than two decades of research have been dedicated to their development for delivery of biomolecular therapeutics, the full potential of CPPs has yet to be realized as the field is hindered by the tendency of CPP-linked cargos to be trapped in endosomes as well as having significant off-target potential in vivo. Using a CPP-adaptor system that reversibly binds cargo thereby overcoming the endosomal entrapment that hampers other CPP methods, bioactive E2 protein was delivered into living cervical cancer cells, resulting in inhibition of cellular proliferation and promotion of cell death in a time- and dose-dependent manner. The results suggest that this nucleic acid- and virus-free delivery method could be harnessed to develop novel, effective protein therapeutics for treatment of cervical cancer.

scholarly journals Human papillomavirus type 18 oncoproteins exert their oncogenicity in esophageal and tongue squamous cell carcinoma cell lines distinctly

2019 ◽  
Author(s):  
Siaw Shi Boon ◽  
Zigui Chen ◽  
Karen Lee Yin Ching ◽  
Liuyang Cai ◽  
Jintao Li ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Tongue Cancer ◽  
Cancer Cell Lines ◽  
Cervical Cancer Cells ◽  
Esophageal Cancer Cell ◽  
Hpv18 E6 ◽  
E6 And E7

Abstract Background: Increasing evidence indicates an etiological role of human papillomavirus (HPV) in head and neck cancers, particularly oropharyngeal squamous cell carcinoma (OPSCC). However, the association between HPV and other cancers, including esophageal and tongue remains unclear. Methods: We compared the molecular characteristics of HPV18 E6 and E7 in esophageal (EC109 and EC9706) and tongue (Tca83) cancer cell lines with reference to cervical cancer (HeLa). We studied the expression of HPV transcripts using Next Generation RNA sequencing. We used small interference RNA (siRNA) against HPV18 oncoproteins to verify their oncogenic roles in molecular signaling, targeting metalloproteases and apoptotic pathways in these cancers. Results: We observed that the HPV transcription profiles of esophageal and tongue cancer cells mimicked that of cervical cancer cells, with notable disruption of E2, and expression of E6, spliced E6 (E6 * ), E7, E1 and L1 transcripts. As with cervical cancer cells, p53 and its downstream transactivation target, p21, were found to be the major targets of E6 in esophageal and tongue cancer cell lines. Intriguingly, E7 preferentially targeted p130 in the two esophageal cancer cell lines, instead of pRb as in cervical cancer. Tca83 exhibited an E7 to E6 transcript ratio comparable to HeLa (cervix), targeted the ERK1/2 and MMP2 pathways, and was dependent on E6 and E7 to survive and proliferate. In contrast, both the esophageal cancer cell lines were distinct from HeLa in these aspects. Conclusion: This is the first study to delineate the transcripts expression and role of HPV18 E6 and E7 in esophageal and tongue cancer cell lines. This findings suggest that HPV18 plays an oncogenic role in inducing these cancers, albeit via distinct pathways than those observed in cervical cancer.

scholarly journals E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer

2020 ◽  
Author(s):  
Ethan L. Morgan ◽  
James A. Scarth ◽  
Molly R. Patterson ◽  
Christopher W. Wasson ◽  
Georgia C. Hemingway ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Human Papillomaviruses ◽  
Signalling Pathway ◽  
Viral Oncoprotein ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7 ◽  
Novel Therapeutic

AbstractHuman papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.

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