scholarly journals Screening and Identification of Potential iNOS Inhibitors to Curtail Cervical Cancer Progression: An in-Silico Drug Repurposing Approach

2021 ◽  
Author(s):  
PAVAN KUMAR POLEBOYINA ◽  
SMITA C PAWAR ◽  
AKBAR PASHA ◽  
RAVINDER DONETI ◽  
SNEHA MALLESWARI POLEBOYINA ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Drug Repurposing ◽  
Reproductive Age ◽  
Endothelial Cell Migration ◽  
Bonding Energy ◽  
Molegro Virtual Docker ◽  
Drug Candidates ◽  
Inos Inhibitors

Abstract Cervical cancer is the second most common cause of cancer deaths in women worldwide and remains the main reason of mortality amongst women of reproductive age in developing countries. Nitric oxide is involved in several physiological functions inclusive of inflammatory and immune responses. However, the function of NO in tumor biology is debatable. The inducibleNOS (iNOS/NOS2) isoform is the oneresponsible to maintain the levels of NO and it exhibits pleotropic effects in various cancer with concentration-dependent pro- and anti-tumor effects.NOS2 triggers angiogenesis and endothelial cell migration in tumors by regulating the levels of vascular endothelial growth factor (VEGF). In drug discovery, drug repurposing involves investigations of approved drug candidates to treat various other diseases. In this study, we used FDA-approved anti-cancer drugs and small molecules to target iNOS and identify a potential selective iNOS inhibitor. The structures of ligands were geometrically optimized, and energy minimized using Hyperchem software. Molecular docking was performed using Molegro virtual docker and ligands were selected based on MolDock score,Rerank score, and H-bonding energy. In the study showed 4 compounds, Degarelix, Goserelin, Triptorelin pamoate, and venetoclax demonstrated excellent binding affinity to NOS2 protein. These compounds exhibited the lowest MolDock score, Rerank score, with better H-bonding energy to NOS2. Based on the results theses ligands project to be promising potential NOS2 inhibitors to curtail cervical cancer progression

scholarly journals IRF-1 Inhibits Angiogenic Activity of HPV16 E6 Oncoprotein in Cervical Cancer

2020 ◽  
Vol 21 (20) ◽  
pp. 7622
Author(s):  
Seung Bae Rho ◽  
Seung-Hoon Lee ◽  
Hyun-Jung Byun ◽  
Boh-Ram Kim ◽  
Chang Hoon Lee
Keyword(s):  
Cervical Cancer ◽  
Cell Growth ◽  
Cancer Progression ◽  
Cellular Proliferation ◽  
Endothelial Cell Migration ◽  
Dependent Manner ◽  
P53 Expression ◽  
Angiogenic Activity ◽  
Hpv16 E6 ◽  
E6 Oncoprotein

HPV16 E6 oncoprotein is a member of the human papillomavirus (HPV) family that contributes to enhanced cellular proliferation and risk of cervical cancer progression via viral infection. In this study, interferon regulatory factor-1 (IRF-1) regulates cell growth inhibition and transcription factors in immune response, and acts as an HPV16 E6-binding cellular molecule. Over-expression of HPV16 E6 elevated cell growth by attenuating IRF-1-induced apoptosis and repressing p21 and p53 expression, but activating cyclin D1 and nuclear factor kappa B (NF-κB) expression. The promoter activities of p21 and p53 were suppressed, whereas NF-κB activities were increased by HPV16 E6. Additionally, the cell viability of HPV16 E6 was diminished by IRF-1 in a dose-dependent manner. We found that HPV16 E6 activated vascular endothelial growth factor (VEGF)-induced endothelial cell migration and proliferation as well as phosphorylation of VEGFR-2 via direct interaction in vitro. HPV16 E6 exhibited potent pro-angiogenic activity and clearly enhanced the levels of hypoxia-inducible factor-1α (HIF-1α). By contrast, the loss of function of HPV16 E6 by siRNA-mediated knockdown inhibited the cellular events. These data provide direct evidence that HPV16 E6 facilitates tumour growth and angiogenesis. HPV16 E6 also activates the PI3K/mTOR signalling cascades, and IRF-1 suppresses HPV16 E6-induced tumourigenesis and angiogenesis. Collectively, these findings suggest a biological mechanism underlying the HPV16 E6-related activity in cervical tumourigenesis.

scholarly journals Interplay Between EGFR and the Platelet-Activating Factor/PAF Receptor Signaling Axis Mediates Aggressive Behavior of Cervical Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Juliana L. Souza ◽  
Karina Martins-Cardoso ◽  
Isabella S. Guimarães ◽  
Andréia C. de Melo ◽  
Angela H. Lopes ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Tumor Biology ◽  
Platelet Activating Factor ◽  
The Cancer Genome Atlas ◽  
Strong Positive Correlation ◽  
Poor Overall Survival ◽  
Cervical Cancer Cells

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in cervical tumors, being correlated with adverse clinical outcomes. EGFR may be activated by a diversity of mechanisms, including transactivation by G-protein coupled receptors (GPCRs). Studies have also shown that platelet-activating factor (PAF), a pro-inflammatory phospholipid mediator, plays an important role in the cancer progression either by modulating the cancer cells or the tumor microenvironment. Most of the PAF effects seem to be mediated by the interaction with its receptor (PAFR), a member of the GPCRs family. PAFR- and EGFR-evoked signaling pathways contribute to tumor biology; however, the interplay between them remains uninvestigated in cervical cancer. In this study, we employed The Cancer Genome Atlas (TCGA) and cancer cell lines to evaluate possible cooperation between EGFR, PAFR, and lysophosphatidylcholine acyltransferases (LPCATs), enzymes involved in the PAF biosynthesis, in the context of cervical cancer. It was observed a strong positive correlation between the expression of EGFR × PAFR and EGFR × LPCAT2 in 306 cervical cancer samples. The increased expression of LPCAT2 was significantly correlated with poor overall survival. Activation of EGFR upregulated the expression of PAFR and LPCAT2 in a MAPK-dependent fashion. At the same time, PAF showed the ability to transactivate EGFR leading to ERK/MAPK activation, cyclooxygenase-2 (COX-2) induction, and cell migration. The positive crosstalk between the PAF-PAFR axis and EGFR demonstrates a relevant linkage between inflammatory and growth factor signaling in cervical cancer cells. Finally, combined PAFR and EGFR targeting treatment impaired clonogenic capacity and viability of aggressive cervical cancer cells more strongly than each treatment separately. Collectively, we proposed that EGFR, LPCAT2, and PAFR emerge as novel targets for cervical cancer therapy.

scholarly journals Metastatic cervical cancer: clinical experience with pembrolizumab application. Case report

2021 ◽  
Vol 23 (2) ◽  
pp. 340-344
Author(s):  
Anna E. Protasova ◽  
Liubov V. Strakh ◽  
Elena I. Lando ◽  
Elena V. Sidorkina
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Treatment Options ◽  
Antiangiogenic Therapy ◽  
Survival Rates ◽  
Reproductive Age ◽  
Steady Increase ◽  
Standard Chemotherapy Regimen ◽  
The Right ◽  
Reproductive Age Group

Cervical cancer (CC) ranks fourth for cancer incidences in women after breast cancer, colorectal cancer and lung cancer. There is a steady increase in the incidence of invasive forms of CC in Russia. Over the past quarter of a century, the mortality rate of reproductive age group women with cervical cancer has increased by 2 times. The standard treatment options for cervical cancer progression were the regime of paclitaxel plus cisplatin (carboplatin). The addition of an antiangiogenic therapy (bevacizumab) to the standard chemotherapy regimen increases overall survival of only 4%. The response to other lines of chemotherapy does not exceed 10% after the therapy using the combination of paclitaxel + carboplatin + bevacizumab. The results of KEYNOTE-158 trial demonstrated objective responses in 91% of CC patients lasting for more than 6 months in case of application of pembrolizumab 200 mg every 3 weeks in cases of PD-L1 expression (CPS1) with acceptable toxicity. The presented clinical case of successful treatment using pembrolizumab in women with PD-L1 expression in metastatic CC has a beneficial effect on further accumulation of experience and could help to choose the right treatment options in order to increase the efficacy of the therapy and to increase the survival rates for this category of patients.

scholarly journals LncRNA PVT1 promotes cervical cancer progression by sponging miR-503 to upregulate ARL2 expression

2021 ◽  
Vol 16 (1) ◽  
pp. 1-13
Author(s):  
Weiwei Liu ◽  
Dongmei Yao ◽  
Bo Huang
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Nude Mouse Model ◽  
Western Blot Assay ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract Cervical cancer (CC) is a huge threat to the health of women worldwide. Long non-coding RNA plasmacytoma variant translocation 1 gene (PVT1) was proved to be associated with the development of diverse human cancers, including CC. Nevertheless, the exact mechanism of PVT1 in CC progression remains unclear. Levels of PVT1, microRNA-503 (miR-503), and ADP ribosylation factor-like protein 2 (ARL2) were measured by quantitative reverse transcription-polymerase chain reaction or western blot assay. 3-(4,5)-Dimethylthiazole-2-y1)-2,5-biphenyl tetrazolium bromide (MTT) and flow cytometry were used to examine cell viability and apoptosis, respectively. For migration and invasion detection, transwell assay was performed. The interaction between miR-503 and PVT1 or ARL2 was shown by dual luciferase reporter assay. A nude mouse model was constructed to clarify the role of PVT1 in vivo. PVT1 and ARL2 expressions were increased, whereas miR-503 expression was decreased in CC tissues and cells. PVT1 was a sponge of miR-503, and miR-503 targeted ARL2. PVT1 knockdown suppressed proliferation, migration, and invasion of CC cells, which could be largely reverted by miR-503 inhibitor. In addition, upregulated ARL2 could attenuate si-PVT1-mediated anti-proliferation and anti-metastasis effects on CC cells. Silenced PVT1 also inhibited CC tumor growth in vivo. PVT1 knockdown exerted tumor suppressor role in CC progression via the miR-503/ARL2 axis, at least in part.

scholarly journals UBE2C Drives Human Cervical Cancer Progression and Is Positively Modulated by mTOR

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 37
Author(s):  
An-Jen Chiang ◽  
Chia-Jung Li ◽  
Kuan-Hao Tsui ◽  
Chung Chang ◽  
Yuan-chin Ivan Chang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Cancer Staging ◽  
Cervical Squamous Cell Carcinoma ◽  
Cancer Cell Proliferation ◽  
Gynecological Malignancy ◽  
In Vivo Experiments ◽  
Ubiquitin Conjugating Enzyme

Cervical cancer is a common gynecological malignancy, accounting for 10% of all gynecological cancers. Recently, targeted therapy for cervical cancer has shown unprecedented advantages. Several studies have shown that ubiquitin conjugating enzyme E2 (UBE2C) is highly expressed in a series of tumors, and participates in the progression of these tumors. However, the possible impact of UBE2C on the progression of cervical squamous cell carcinoma (CESC) remains unclear. Here, we carried out tissue microarray analysis of paraffin-embedded tissues from 294 cervical cancer patients with FIGO/TNM cancer staging records. The results indicated that UBE2C was highly expressed in human CESC tissues and its expression was related to the clinical characteristics of CESC patients. Overexpression and knockdown of UBE2C enhanced and reduced cervical cancer cell proliferation, respectively, in vitro. Furthermore, in vivo experiments showed that UBE2C regulated the expression and activity of the mTOR/PI3K/AKT pathway. In summary, we confirmed that UBE2C is involved in the process of CESC and that UBE2C may represent a molecular target for CESC treatment.

scholarly journals Splicing Genomics Events in Cervical Cancer: Insights for Phenotypic Stratification and Biomarker Potency

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 130
Author(s):  
Flavia Zita Francies ◽  
Sheynaz Bassa ◽  
Aristotelis Chatziioannou ◽  
Andreas Martin Kaufmann ◽  
Zodwa Dlamini
Keyword(s):  
Cervical Cancer ◽  
Alternative Splicing ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapy Resistance ◽  
Splicing Factors ◽  
Aberrant Splicing ◽  
Molecular Alteration ◽  
Common Cancer ◽  
Potential Biomarkers

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets.

scholarly journals Low-dose naltrexone plays antineoplastic role in cervical cancer progression through suppressing PI3K/AKT/mTOR pathway

2021 ◽  
Vol 14 (4) ◽  
pp. 101028
Author(s):  
Ning Liu ◽  
Limei Yan ◽  
Fengping Shan ◽  
Xiaonai Wang ◽  
Na Qu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Low Dose ◽  
Mtor Pathway ◽  
Low Dose Naltrexone
Sign in / Sign up

Export Citation Format

Share Document