An In Silico Appraisal of Azoic and Disulphide Derivatives for Anticancer Activity Against HPV E6 Oncoprotein to Medicate Cervical Cancer

2014 ◽  
Vol 17 (1) ◽  
pp. 38-46 ◽  
Author(s):  
Arpita Choudhury ◽  
Manabendra Choudhury ◽  
Pankaj Chetia ◽  
Abhishek Chowdhury ◽  
Anupam Talukdar
Keyword(s):  
Cervical Cancer ◽  
Anticancer Activity ◽  
In Silico ◽  
Hpv E6 ◽  
E6 Oncoprotein

scholarly journals In Silico Approaches: A Way to Unveil Novel Therapeutic Drugs for Cervical Cancer Management

2021 ◽  
Vol 14 (8) ◽  
pp. 741
Author(s):  
Diana Gomes ◽  
Samuel Silvestre ◽  
Ana Paula Duarte ◽  
Aldo Venuti ◽  
Christiane P. Soares ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Small Molecules ◽  
In Silico ◽  
Access To Health Services ◽  
Cancer Management ◽  
Hpv E6 ◽  
Therapeutic Drugs ◽  
E6 Oncoprotein ◽  
Access To Health ◽  
E6 And E7

Cervical cancer (CC) is the fourth most common pathology in women worldwide and presents a high impact in developing countries due to limited financial resources as well as difficulties in monitoring and access to health services. Human papillomavirus (HPV) is the leading cause of CC, and despite the approval of prophylactic vaccines, there is no effective treatment for patients with pre-existing infections or HPV-induced carcinomas. High-risk (HR) HPV E6 and E7 oncoproteins are considered biomarkers in CC progression. Since the E6 structure was resolved, it has been one of the most studied targets to develop novel and specific therapeutics to treat/manage CC. Therefore, several small molecules (plant-derived or synthetic compounds) have been reported as blockers/inhibitors of E6 oncoprotein action, and computational-aided methods have been of high relevance in their discovery and development. In silico approaches have become a powerful tool for reducing the time and cost of the drug development process. Thus, this review will depict small molecules that are already being explored as HR HPV E6 protein blockers and in silico approaches to the design of novel therapeutics for managing CC. Besides, future perspectives in CC therapy will be briefly discussed.

scholarly journals Survivin Clinical Features in Cervical Cancer

2017 ◽  
Vol 1 (1) ◽  
pp. 6
Author(s):  
Miftakh Nur Rahman ◽  
Chyntia Resti Wijaya ◽  
Maria Novalentina
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Critical Role ◽  
Survivin Expression ◽  
Hpv Infection ◽  
Cytotoxic T Cell ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Cycle Dependent ◽  
Oncogenic Protein

Cervical cancer is the primary lethal malignancy for women worldwide, but because it develops over time, it would be one of the most preventable types of cancer. Dysregulation of apoptosis in cells plays a critical role in the malignancy development. Survivin is the smallest inhibitor apoptotic protein (IAP) which has an important part in regulating cell division and inhibitor of apoptosis. This review focused on survivin features in cervical cancer from mechanisms of malignancy relationship to human papillomavirus (HPV) infection through E6 oncogenic protein, role as a biomarker in diagnosis, prognosis, staging and prediction of metastasis, and also as a target for therapy. Regulation of survivin divided into two main groups; cell cycle dependent and cell cycle independent pathway to maintain life and death balance. Survivin expression is upregulated by E6 protein simultaneously repressing p53. Thus cancerous cervical tissue developed. Survivin is also upregulated in hypoxia, a common condition in many tumors and increased angiogenesis. Survivin plays a major role in chemotherapy and radiation resistance in many cases of cervical cancer. As a target of therapy, survivin has a promising performance, suggested very specific and no issue of resistance and also reducing resistance to chemo and radiation therapy. The goal of treatment is to lower survivin expression through transcription inhibition, immunotherapy based on cytotoxic T cell (CTL) activity and gene therapy.  Keywords: cervical cancer, survivin, HPV E6 oncoprotein, therapy

Role of molecular biomarker human papilloma virus (HPV) E6 oncoprotein in cervical cancer screening

2020 ◽  
Vol 158 (3) ◽  
pp. 590-596
Author(s):  
Rifat Ara ◽  
Sabera Khatun ◽  
Shahana Pervin ◽  
Munira Jahan ◽  
Umme Shahera ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Screening ◽  
Human Papilloma Virus ◽  
Cervical Cancer Screening ◽  
Molecular Biomarker ◽  
Papilloma Virus ◽  
Hpv E6 ◽  
E6 Oncoprotein

scholarly journals The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 521 ◽  
Author(s):  
Joaquin Manzo-Merino ◽  
Alfredo Lagunas-Martínez ◽  
Carla Contreras-Ochoa ◽  
Marcela Lizano ◽  
Leonardo Castro-Muñoz ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
Immune Surveillance ◽  
Dependent Manner ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Inflammatory State ◽  
Cervical Cancer Development ◽  
Carcinogenic Process

Persistent infection with high-risk Human Papillomavirus (HR-HPV) is the main requisite for cervical cancer development. Normally, HPV is limited to the site of infection and regulates a plethora of cellular elements to avoid the immune surveillance by inducing an anti-inflammatory state, allowing the progress through the viral cycle and the carcinogenic process. Recent findings suggest that the AT-hook transcriptional factor AKNA could play a role in the development of cervical cancer. AKNA is strongly related to the expression of co-stimulatory molecules such CD40/CD40L to achieve an anti-tumoral immune response. To date, there is no evidence demonstrating the effect of the HPV E6 oncoprotein on the AT-hook factor AKNA. In this work, minimal expression of AKNA in cervical carcinoma compared to normal tissue was found. We show the ability of E6 from high-risk HPVs 16 and 18 to interact with and down-regulate AKNA as well as its co-stimulatory molecule CD40 in a proteasome dependent manner. We also found that p53 interacts with AKNA and promotes AKNA expression. Our results indicate that the de-regulation of CD40 and AKNA is induced by the HPV E6 oncoprotein, and this event involves the action of p53 suggesting that the axis E6/p53A/AKNA might play an important role in the de-regulation of the immune system during the carcinogenic process induced by HR-HPV.

scholarly journals In silico prediction of structural changes in human papillomavirus type 16 (HPV16) E6 oncoprotein and its variants

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Hugo Alberto Rodríguez-Ruiz ◽  
Olga Lilia Garibay-Cerdenares ◽  
Berenice Illades-Aguiar ◽  
Sarita Montaño ◽  
Xiaowei Jiang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Asian American ◽  
In Silico ◽  
Structural Changes ◽  
3D Structure ◽  
Experimental Studies ◽  
Structural Disorder ◽  
Biological Behavior ◽  
Hpv16 E6 ◽  
E6 Oncoprotein

Abstract Background HPV16 infection is one of the main risk factors involved in the development of cervical cancer, mainly due to the high oncogenic potential of the viral proteins E6 and E7, which are involved in the different processes of malignant transformation. There is a broad spectrum of intratypical variation of E6, which is reflected in its high diversity, biological behavior, global distribution and risk of causing cervical cancer. Experimental studies have shown that the intratypical variants of the protein E6 from the European variants (E-G350, E-A176/G350, E-C188/G350) and Asian-American variants (AAa and AAc), are capable of inducing the differential expression of genes involved in the development of cervical cancer. Results An in silico analysis was performed to characterize the molecular effects of these variations using the structure of the HPV16 E6 oncoprotein (PDB: 4XR8; chain H) as a template. In particular, we evaluated the 3D structures of the intratypical variants by structural alignment, ERRAT, Ramachandran plots and prediction of protein disorder, which was further validated by molecular dynamics simulations. Our results, in general, showed no significant changes in the protein 3D structure. However, we observed subtle changes in protein physicochemical features and structural disorder in the N- and C-termini. Conclusions Our results showed that mutations in the viral oncogene E6 of six high-risk HPV16 variants are effectively neutral and do not cause significant structural changes except slight variations of structural disorder. As structural disorder is involved in rewiring protein-protein interactions, these results suggest a differential pattern of interaction of E6 with the target protein P53 and possibly different patterns of tumor aggressiveness associated with certain types of variants of the E6 oncoprotein.

scholarly journals JAK2 Inhibition Impairs Proliferation and Sensitises Cervical Cancer Cells to Cisplatin-Induced Cell Death

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1934 ◽  
Author(s):  
Ethan L. Morgan ◽  
Andrew Macdonald
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Therapeutic Potential ◽  
Early Stage ◽  
Janus Kinase ◽  
Oral Cancers ◽  
Jak2 Inhibitor ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Cervical Cancer Cells

Persistent infection with high-risk human papillomavirus (HPV) is the underlying cause of ~5% of all human cancers, including the majority of cervical carcinomas and many other ano-genital and oral cancers. A major challenge remains to identify key host targets of HPV and to reveal how they contribute to virus-mediated malignancy. The HPV E6 oncoprotein aberrantly activates the signal transducer and activator of transcription 3 (STAT3) transcription factor and this is achieved by a virus-driven increase in the levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in HPV positive cervical cancers cells. Crucially, STAT3 activity is essential for the proliferation and survival of cervical cancer cells, suggesting that targeting STAT3 may have therapeutic potential. Unfortunately, the development of direct STAT3 inhibitors has been problematic in the clinic due to toxicity issues identified in early stage trials. To overcome this issue, we focused on the protein Janus kinase 2 (JAK2), which phosphorylates STAT3 and is essential for STAT3 activation. Here, we demonstrate that inhibiting JAK2 reduces cell proliferation and induces apoptosis in HPV transformed cervical cancer cells. We further establish that this is due to inhibition of phosphorylation of the JAK2 substrates STAT3 and STAT5. Finally, we demonstrate that the clinically available JAK2 inhibitor Ruxolitinib synergises with cisplatin in inducing apoptosis, highlighting JAK2 as a promising therapeutic target in HPV-driven cancers.

scholarly journals Role of Cdk1 in the p53-Independent Abrogation of the Postmitotic Checkpoint by Human Papillomavirus E6

2014 ◽  
Vol 89 (5) ◽  
pp. 2553-2562 ◽  
Author(s):  
Weifang Zhang ◽  
Yingwang Liu ◽  
Ning Zhao ◽  
Hanxiang Chen ◽  
Lijun Qiao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Drug Targets ◽  
Cell Cycle Checkpoints ◽  
Wild Type ◽  
Hpv E6 ◽  
E6 Oncoprotein ◽  
Shed Light

ABSTRACTSpecific types of human papillomavirus (HPV) are strongly associated with the development of cervical carcinoma. The HPV E6 oncoprotein from HPV degrades p53 and abrogates cell cycle checkpoints. Nonetheless, functional p53 has been observed in cervical cancer. We have previously identified a p53-independent function of E6 in attenuating the postmitotic G1-like checkpoint that can lead to polyploidy, an early event during cervical carcinogenesis that predisposes cells to aneuploidy. How E6 promotes cell cycle progression in the presence of p53 and its target, p21, remains a mystery. In this study, we examined the expression of cell cycle-related genes in cells expressing wild-type E6 and the mutant that is defective in p53 degradation but competent in abrogating the postmitotic checkpoint. Our results demonstrated an increase in the steady-state levels of G1- and G2-related cyclins/Cdks in E6-expressing keratinocytes. Interestingly, only Cdk1 remained active in E6 mutant-expressing cells while bypassing the postmitotic checkpoint. Furthermore, the downregulation of Cdk1 impaired the ability of both wild-type and mutant E6 to induce polyploidy. Our study thus demonstrated an important role for Cdk1, which binds p21 with lower affinity than Cdk2, in abrogating the postmitotic checkpoint in E6-expressing cells. We further show that E2F1 is important for E6 to upregulate Cdk1. Moreover, reduced nuclear p21 localization was observed in the E6 mutant-expressing cells. These findings shed light on the mechanisms by which HPV induces genomic instability and hold promise for the identification of drug targets.IMPORTANCEHPV infection is strongly associated with the development of cervical carcinoma. HPV encodes an E6 oncoprotein that degrades the tumor suppressor p53 and abrogates cell cycle checkpoints. Nonetheless, functional p53 has been observed in cervical cancer. We have recently demonstrated a p53-independent abrogation of the postmitotic checkpoint by HPV E6 that induces polyploidy. However, the mechanism is not known. In this study, we provide evidence that Cdk1 plays an important role in this process. Previously, Cdk2 was thought to be essential for the G1/S transition, while Cdk1 only compensated its function in the absence of Cdk2. Our studies have demonstrated a novel role of Cdk1 at the postmitotic G1-like checkpoint in the presence of Cdk2. These findings shed light on the mechanisms by which HPV induces genomic instability and hold promise for the identification of drug targets.

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