Resveratrol Suppresses the Growth and Metastatic Potential of Cervical Cancer through Inhibiting STAT3Tyr705 Phosphorylation

2020 ◽  
Author(s):  
Xiaodong Sun ◽  
Qianqian Xu ◽  
Lian Zeng ◽  
Lixia Xie ◽  
Qiang Zhao ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Molecular Docking ◽  
Hela Cells ◽  
Protein Level ◽  
Metastatic Potential ◽  
Dependent Manner ◽  
Resveratrol Treatment ◽  
Siha Cells ◽  
Tumor Tissues ◽  
E Cadherin

Abstract Background : The aberrant STAT3 signaling promotes initiation and progression of human cancers by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. This study aims to investigate the role of STAT3 and its phosphorylation status in resveratrol-mediated suppression of cervical cancer. Methods : The effects of resveratrol on cervical tumor growth were also determined by examining the tumor tissues and their histological changes and the volume and weight of tumor tissues grown from Hela cells injected in female athymic BALB/C nude mice following the pretreatment regimen and the treatment regimen. Resveratrol structure and targets interaction virtual screening was performed using molecular docking program Autodock Vina. The phosphorylated STAT3, EMT molecular markers and ECM degradation enzymes protein levels were determined using Western blotting. Results : Proliferation and the colony formation of Hela cells were inhibited after resveratrol treatment in both dose- and time- dependent manner. Resveratrol inhibited migration and invasion of Hela cells. Molecular docking analysis showed that resveratrol interacted with STAT3 at a pocket composed of 11 amino acidic residues. Treatment with resveratrol resulted in decreases in the level of phosphorylation of STAT3 at Tyr705 but not Ser727, and no obvious changes in the protein level of STAT3 in Hela cells and SiHa cells. Pretreatment or treatment with resveratrol resulted in decreases in the IL-6-induced phosphorylation level of STAT3Tyr705 in Hela cells and SiHa cells, compared with those of treatment with IL-6. Reduced STAT3Tyr705 phosphorylation after STAT3 inhibitors S3I201 enhanced inhibition of invasion potential of Hela cells and SiHa cells treated with Resveratrol. Resveratrol decreases the N-Cadherin, Vimentin, MMP-3, MMP-13 protein level and increases the E-Cadherin protein level in a dose-dependent manner. The tumor size, volume, and weight, and the N-Cadherin, Vimentin, MMP-3, and MMP-13 protein level were significantly decreased, and the E-Cadherin protein level was increased, and the tumors were histologically damaged as revealed by H&E staining in both the resveratrol pretreatment group and the resveratrol treatment group and the magnitude of changes was higher in the former than that of the latter. Conclusion : Resveratrol inhibits growth and metastatic potential of cervical cancer through blocking STAT3Tyr705 phosphorylation.

scholarly journals Influence of icariin on inflammation, apoptosis, invasion, and tumor immunity in cervical cancer by reducing the TLR4/MyD88/NF-κB and Wnt/β-catenin pathways

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chunyang Li ◽  
Shuangqing Yang ◽  
Huaqing Ma ◽  
Mengjia Ruan ◽  
Luyan Fang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Underlying Mechanism ◽  
Tissue Growth ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Siha Cells ◽  
Cervical Cancer Cells

Abstract Background Cervical cancer is a type of the most common gynecology tumor in women of the whole world. Accumulating data have shown that icariin (ICA), a natural compound, has anti-cancer activity in different cancers, including cervical cancer. The study aimed to reveal the antitumor effects and the possible underlying mechanism of ICA in U14 tumor-bearing mice and SiHa cells. Methods The antitumor effects of ICA were investigated in vivo and in vitro. The expression of TLR4/MyD88/NF-κB and Wnt/β-catenin signaling pathways were evaluated. Results We found that ICA significantly suppressed tumor tissue growth and SiHa cells viability in a dose-dependent manner. Also, ICA enhanced the anti-tumor humoral immunity in vivo. Moreover, ICA significantly improved the composition of the microbiota in mice models. Additionally, the results clarified that ICA significantly inhibited the migration, invasion capacity, and expression levels of TGF-β1, TNF-α, IL-6, IL-17A, IL-10 in SiHa cells. Meanwhile, ICA was revealed to promote the apoptosis of cervical cancer cells by down-regulating Ki67, survivin, Bcl-2, c-Myc, and up-regulating P16, P53, Bax levels in vivo and in vitro. For the part of mechanism exploration, we showed that ICA inhibits the inflammation, proliferation, migration, and invasion, as well as promotes apoptosis and immunity in cervical cancer through impairment of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways. Conclusions Taken together, ICA could be a potential supplementary agent for cervical cancer treatment.

scholarly journals Baicalein Inhibits the Proliferation of Cervical Cancer Cells Through the GSK3β-Dependent Pathway

2018 ◽  
Vol 26 (4) ◽  
pp. 645-653 ◽  
Author(s):  
Xiaoling Wu ◽  
Zhiqin Yang ◽  
Huimin Dang ◽  
Huixia Peng ◽  
Zhijun Dai
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cyclin D1 ◽  
Cancer Cells ◽  
Hela Cells ◽  
Glycogen Synthase ◽  
Dependent Manner ◽  
Cervical Cancer Cells ◽  
Dose Dependent ◽  
Dependent Pathway

Baicalein, a flavonoid derived from the root of Scutellaria baicalensis, has been reported to possess multiple pharmacological activities, such as anticancer and anti-inflammatory properties. This study investigated the effect of baicalein in cervical cancer cells. Cell growth curve and MTT assay were performed and revealed that baicalein inhibited the proliferation of SiHa and HeLa cells in a dose-dependent manner. We further found that baicalein arrested the cell cycle of SiHa and HeLa cells at the G0/G1 phase by suppressing the expression of cyclin D1 through the downregulation of phosphorylated protein kinase B (p-AKT) and phosphorylated glycogen synthase kinase 3β (p-GSK3β) according to FACS assays and Western blotting. Moreover, when CHIR-99021, a GSK3β inhibitor, was added to baicalein-treated SiHa cells, the expression of cyclin D1 was recovered, and cell proliferation was promoted. In conclusion, these data indicated that baicalein suspended the cell cycle at the G0/G1 phase via the downregulation of cyclin D1 through the AKT‐GSK3β signaling pathway and further inhibited the proliferation of SiHa and HeLa cervical cancer cells.

scholarly journals Syringin exhibits anticancer effects in HeLa human cervical cancer cells by inducing apoptosis, cell cycle arrest and inhibition of cell migration

2016 ◽  
Vol 11 (4) ◽  
pp. 838 ◽  
Author(s):  
Ning Xia
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Migration ◽  
Cell Cycle Arrest ◽  
Hela Cells ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
Cervical Cancer Cells ◽  
Human Cervical Cancer Cells ◽  
Human Cervical Cancer

<p class="Abstract">The present study was aimed at to demonstrate the antitumor effects of syringin in HeLa human cervical cancer cells. Its effects on apoptosis, cell cycle phase distribution as well as on cell migration were also examined. The effect on cell proliferation was evaluated by MTT assay, while as effects on colony formation were assessed using clonogenic assay. Syringin inhibited cancer cell growth in HeLa cells in a time-dependent as well as in a concentration-dependent manner. Syringin also led to inhibition of colony formation efficacy with complete suppression at 100 µM drug dose. Syringin could induce G2/M cell cycle arrest along with slight sub-G1 cell cycle arrest. HeLa cells began to emit red fluorescence as the dose of syringin increased from 0 µM in vehicle control to 100 µM. Syringin also inhibited cell migration in a dose-dependent manner with 100 µM dose of syringin leading to 100% inhibition of cell migration.</p><p> </p>

scholarly journals Hesperidin Induces Mitochondria Mediated Intrinsic Apoptosis in HPV-positive Cervical Cancer Cells via Regulation of E6/p53 Expression

2020 ◽  
Author(s):  
Fang Ren ◽  
Gong Zhang ◽  
Caiyu Li ◽  
Gailing Li ◽  
Yuan Cao ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Protein Level ◽  
Potential Candidate ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
P53 Expression ◽  
Cervical Cancer Cells ◽  
Apoptotic Proteins

Abstract Background: Hesperetin, an active compound found in citrus fruits, possesses antiproliferative effects toward several types of cancer cell lines, including cervical cancer. In this study, we explore the antitumor effects of Hesperetin on the human cervical cancer human papilloma virus (HPV)-positive (CaSki and HeLa) and HPV-negative (C-33A) cell lines and further elucidated the underlying mechanisms of this action. Methods: Cell viability and proliferation was measured by the MTT assay and 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay, respectively. dUTP-fluorescein nick end-labeling (TUNEL) staining, Annexin V‑fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining and flow cytometry was used to assess the degree of apoptosis. JC-1 staining assay was used to evaluate the change of mitochondrial membrane potential (ΔΨm) and Western blot assays were used to determine apoptosis-related factors at protein level. Results: Hesperetin (100, 200 and 400 μM) exhibited a significant exclusive inhibitory effect against the growth of HPV-infected CaSki and HeLa cancer cells via induction of apoptosis in a concentration-dependent manner, while it was almost not active in HPV-negative C-33A cancer cells and normal cervix epithelial H8 cells. Moreover, this antitumor effect executed by Hesperetin was associated with disruption of ΔΨm, the release of cytochrome c from mitochondria, activation of pro-apoptotic proteins (Bax, cleaved caspase-3 and caspase-9) and inhibition of anti-apoptotic proteins (Bcl-2). During this process, cleaved caspase-8 remained unchanged. In addition, Hesperetin led to a downregulation of E6 oncoprotein expression and upregulation of tumor suppressor protein p53 level. Conclusions: Collectively, these results implicated that Hesperetin can induce apoptosis of HPV‑positive cervical cancer cells via a mitochondria-mediated intrinsic signaling pathway, together with the repression of E6 and enhancement of p53 protein level, indicating Hesperetin may be considered as a potential candidate for the development of innovative anti-HPV cervical cancer agents.

scholarly journals Nucleolin Promotes Cisplatin Resistance in Cervical Cancer by the YB1-MDR1 Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Jing Ke ◽  
Chunming Gu ◽  
Heyan Zhang ◽  
Yang Liu ◽  
Wenhao Zhang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Drug Resistance ◽  
Hela Cells ◽  
Protein Level ◽  
Molecular Mechanisms ◽  
Cisplatin Resistance ◽  
Mdr1 Gene ◽  
Luciferase Reporter ◽  
Drug Efflux ◽  
Cell Line Hela

Purpose. Cervical cancer is the fourth most common cancer in women worldwide and is the main cause of cancer-related deaths in women. Cisplatin (DDP) is one of the major chemotherapeutic drugs for cervical cancer patients. But, drug resistance limits the effectiveness of cancer therapy. Nucleolin (NCL) is a nucleocytoplasmic multifunctional protein involved in the development of cancer. It has been reported that NCL may be a potential target for modulation of drug resistance. However, the precise molecular mechanisms are poorly understood. Materials and Methods. Human cervical cancer Hela cells and their cisplatin-resistant cell line Hela/DDP were used in this study. The protein level of NCL in cervical cancer cells was measured by western blot analysis. Hela cells and Hela/DDP cells were transfected with NCL overexpression plasmid or NCL siRNA separately. MTT and EdU assay were performed to evaluate the cell viability and sensitivity to cisplatin. The drug efflux function of MDR1 protein was assessed by intracellular rhodamine-123 accumulation assay.The promoter activity of MDR1 was assessed by using a dual-luciferase reporter assay. Results. We found that the protein level of NCL was elevated in Hela/DDP cells. Overexpression of NCL increased cervical cancer cell proliferation and attenuated the sensitivity to cisplatin. Overexpression of NCL increased Multidrug resistance (MDR1) gene expression and drug efflux. Our results demonstrated that NCL was highly related with cisplatin resistance in cervical cancer. NCL played an important role in MDR1 gene transcription through regulation of the transcription factor YB1. Conclusion. Our findings revealed the novel role of NCL in cisplatin-resistant cervical cancer and NCL may be a potential therapeutic target for chemoresistance.

Amiodarone’s major metabolite, desethylamiodarone, induces apoptosis in human cervical cancer cells

2018 ◽  
Vol 96 (10) ◽  
pp. 1004-1011 ◽  
Author(s):  
Zita Bognar ◽  
Katalin Fekete ◽  
Rita Bognar ◽  
Aliz Szabo ◽  
Reka A. Vass ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Hela Cell ◽  
Cancer Cells ◽  
Hela Cells ◽  
Dead Cell ◽  
Dependent Manner ◽  
Cervical Cancer Cells ◽  
Human Cervical Cancer Cells ◽  
Human Cervical Cancer

Previously, we found that desethylamiodarone (DEA) may have therapeutic potentiality in bladder cancer. In this study, we determined its effects on human cervical cancer cells (HeLa). Cell viability was evaluated by Muse Cell Count & Viability Assay; cell apoptosis was detected by Muse Annexin V & Dead Cell Assay. Cell cycle was flow cytometrically determined by Muse Cell Cycle Kit and the morphological changes of the cells were observed under a fluorescence microscope after Hoechst 33342 staining. The changes in the expression levels of apoptosis-related proteins in the HeLa cells were assessed by immunoblot. Our results showed that DEA significantly inhibited the proliferation and viability of HeLa cells and induced apoptosis in vitro in dose-dependent and also in cell cycle-dependent manner because DEA induced G0/G1 phase arrest in the HeLa cell line. We found that DEA treatment downregulated the expression of phospho-Akt and phospho-Bad. In addition, DEA could downregulate expression of Bcl-2, upregulate Bax, and induce cytochrome c release. Our results indicate that DEA might have significance as an anti-tumor agent against human cervical cancer.

scholarly journals Potential Role of DEC1 in Cervical Cancer Cells Involving Overexpression and Apoptosis

2020 ◽  
Vol 2 (1) ◽  
pp. 26-38
Author(s):  
Fuyuki Sato ◽  
Ujjal K. Bhawal ◽  
Nao Sugiyama ◽  
Shoko Osaki ◽  
Kosuke Oikawa ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Hela Cells ◽  
Epithelial Mesenchymal Transition ◽  
Stem Cell Markers ◽  
Mesenchymal Transition ◽  
Helix Loop Helix ◽  
Siha Cells ◽  
Cervical Cancer Cells ◽  
Human Cervical Cancer

Basic helix-loop-helix (BHLH) transcription factors differentiated embryonic chondrocyte gene 1 (DEC1) and gene 2 (DEC2) regulate circadian rhythms, apoptosis, epithelial mesenchymal transition (EMT), invasions and metastases in various kinds of cancer. The stem cell markers SOX2 and c-MYC are involved in the regulation of apoptosis and poor prognosis. In cervical cancer, however, their roles are not well elucidated yet. To determine the function of these genes in human cervical cancer, we examined the expression of DEC1, DEC2, SOX2 and c-MYC in human cervical cancer tissues. In immunohistochemistry, they were strongly expressed in cancer cells compared with in non-cancerous cells. Notably, the strong rate of DEC1 and SOX2 expressions were over 80% among 20 cases. We further examined the roles of DEC1 and DEC2 in apoptosis. Human cervical cancer HeLa and SiHa cells were treated with cisplatin—HeLa cells were sensitive to apoptosis, but SiHa cells were resistant. DEC1 expression decreased in the cisplatin-treated HeLa cells, but had little effect on SiHa cells. Combination treatment of DEC1 overexpression and cisplatin inhibited apoptosis and affected SOX2 and c-MYC expressions in HeLa cells. Meanwhile, DEC2 overexpression had little effect on apoptosis and on SOX2 and c-MYC expressions. We conclude that DEC1 has anti-apoptotic effects and regulates SOX2 and c-MYC expressions on apoptosis.

scholarly journals Glucocappasalin Induces G2/M-Phase Arrest, Apoptosis, and Autophagy Pathways by Targeting CDK1 and PLK1 in Cervical Carcinoma Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Guangya Xu ◽  
Xueling Yan ◽  
Zhongjia Hu ◽  
Lulu Zheng ◽  
Ke Ding ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cervical Carcinoma ◽  
Hela Cells ◽  
Carcinoma Cells ◽  
Dependent Manner ◽  
Cycle Arrest ◽  
Phase Arrest ◽  
M Phase

Glucocappasalin (GCP), a natural product derived from the seeds of Descurainia sophia (L.) Webb. ex Prantl, exhibits potential antitumor activity in HeLa cervical carcinoma cells. In this study, we investigated the anti-cervical cancer property of GCP through the induction of cell cycle arrest, apoptosis, and autophagy in vitro and in vivo, and elucidated the underlying molecular mechanisms. We demonstrated that treatment with GCP inhibited the growth of HeLa, Siha, and Ca Ski cell lines in a dose-dependent manner, with HeLa cells displaying particular sensitivity to the GCP treatment. Subsequently, the expression of cyclin-dependent kinase 1 (CDK1) and polo like kinase 1 (PLK1) were evaluated in HeLa cells using the CDK1 kinase assay kit, the fluorescence polarization assay, real-time quantitative PCR, and western blotting. Our results demonstrate that GCP could be employed to attenuate the expression of CDK1 and PLK1 in a dose- and time-dependent manner. The complementary results obtained by flow cytometry and western blotting allowed us to postulate that GCP may exhibit its antitumor effects by inducing G2/M cell cycle arrest. Moreover, HeLa cells treated with GCP exhibited a loss in mitochondrial membrane potential, together with the activation of caspases 3 and 9, and poly ADP-ribose polymerase (PARP). Additionally, we found that GCP could increase the formation of acidic vesicular organelles (AVOs), as well as the levels of Beclin1, LC3-II, p62, and Atg5 proteins in HeLa cells. Further studies indicated that GCP triggered autophagy via the suppression of the PI3K/AKT/mTOR signaling pathways. The autophagy inhibitor 3-methyladenine (3-MA) was used to determine whether autophagy affects the apoptosis induced by GCP. Interestingly, the inhibition of autophagy attenuated apoptosis. In vivo anti-tumor experiments indicated that GCP (60 mg/kg, i.p.) markedly reduced the growth of HeLa xenografts in nude mice without apparent toxicity. Taken together, we demonstrate that GCP induces cell cycle G2/M-phase arrest, apoptosis, and autophagy by acting on the PI3K/AKT/mTOR signaling pathways in cervical carcinoma cells. Thus, GCP may represent a promising agent in the eradication of cervical cancer.

scholarly journals Microsecond Pulse Electrical Stimulation Inhibit the Proliferation of Cervical Cancer Cells through the Ras-Raf-MAPK Pathway

2020 ◽  
Author(s):  
Xiaoyue Xu ◽  
Shiyan Wang ◽  
Tingting Cao ◽  
Bing Xie ◽  
Xiuli Sun ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Electrical Stimulation ◽  
Pelvic Floor ◽  
Cancer Cells ◽  
Hela Cells ◽  
Mapk Pathway ◽  
Cell Counting ◽  
Proliferation Inhibition ◽  
Siha Cells ◽  
Cervical Cancer Cells

Abstract Objective: Using microsecond pulsed electrical stimulation (μsPES) applied to treat pelvic floor dysfunctions(PFDs) to stimulate the cervical cancer cells. To explore the effects and mechanisms of different μsPES on the proliferation of cervical cancer cells. Methods: Scheme #1 (1/4/1 Hz, 270/230/270 μs, 30min), scheme #2 (30 Hz, 500 μs, 20min), and scheme #3 (50 Hz, 250 μs, 20min) were selected from a pelvic floor rehabilitation therapy instrument. Three μsPES-based schemes each at 20, 40, 60, 80, and 100 mA current values were used to stimulate SiHa cells and HeLa cells. Cell counting kit-8 (CCK-8) assay was used to detect cell proliferation. Scheme #2 at 100 mA current was employed to stimulate SiHa cells and HeLa cells and then western blotting was applied to detect the expressions of the Ras-Raf-MAPK pathway. Results: Current with higer frequency and current intensity tended to have a more proliferation inhibition on cervical cancer cells. μsPES had a stronger proliferation inhibition in SiHa cells than HeLa cells. The expressions of MAPK, MEK1/2 and p-MEK1/2, Raf and p-Raf, Ras protein were significantly decreased in SiHa cells and HeLa cells compared with the control. The p-MAPK was up-regulated in HeLa cells while down-regulated in SiHa cells. Conclusions: μsPES could inhibit the proliferation of cervical cancer cells by suppressing the Ras-Raf-MAPK pathway. The μsPES applied for functional rehabilitation of pelvic floor nerves and muscles is safe for cervical cancer patients at the cellular level

scholarly journals 4SC-202 Exerts An Anti-tumor Effect in Cervical Cancer By Targeting PRLR Signaling Pathway

2021 ◽  
Author(s):  
Huijuan Zhang ◽  
Mingxia Li ◽  
Wen Yang ◽  
Mingxia Ye ◽  
Hua Li ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Growth ◽  
Western Blotting ◽  
Prolactin Receptor ◽  
Cell Cycle Distribution ◽  
Dependent Manner ◽  
Siha Cells ◽  
Serum Biochemical

Abstract The aim of the present study is to investigate whether 4SC-202, a selective class I histone deacetylase inhibitor (HDACi), plays an anti-tumor role in cervical cancer (CC) by targeting prolactin receptor (PRLR). CCK-8 and colony formation assays were used to evaluate the effects of 4SC-202 on the proliferation of CC cells in vitro. Effects of 4SC-202 on the cell cycle distribution and apoptosis in SiHa cells were determined by flow cytometry and western blotting, respectively. Immunofluorescence and western blotting were performed to detect the activities of PRLR-related pathways and PRLR expression in CC cells. A xenograft tumor model in nude mice was established to examine effects of 4SC-202 on the tumor growth, apoptosis and PRLR-related pathways in vivo. The biochemical analyzer and H&E staining were used to detect the serum biochemical indexes and organ toxicity. 4SC-202 inhibited the proliferation of CC cells (SiHa, HeLa, and CaSki) in vitro in a time- and dose-dependent manner. SiHa cells were treated with 1 or 5 μM 4SC-202 for 72 h and then subjected to various functional assays. The assays showed that 4SC-202 significantly induced G2/M phase arrest and apoptosis, while inhibiting the activities of PRLR-related pathways and PRLR expression. In addition, 4SC-202 reduced tumor growth and induced apoptosis in vivo. 4SC-202 down-regulated the expression of PRLR and activities of PRLR-related pathways in the mouse model, displayed no effects on serum biochemical indicators and caused no toxicity to mouse organs. This finding suggests that 4SC-202 may serve as a novel therapeutic agent for CC.

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