Cervical Cancer Cell Survival Research Articles

MiR-21 Regulates Growth and Migration of Cervical Cancer Cells by RECK Signaling Pathway.

Expression of miR-21 has been found to be altered in almost all types of cancers, and it has been classified as an oncogenic microRNA. In addition, the expression of tumor suppressor gene RECK is associated with miR-21 overexpression in high-grade cervical lesions. In the present study, we analyze the role of miR-21 in RECK gene regulation in cervical cancer cells. To identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression using siRNAs. We analyzed the expression of miR-21 and RECK, as well as functional effects on cell proliferation and migration. We found that in cervical cancer cells, there was an inverse correlation between miR-21 expression and RECK mRNA and protein expression. SiRNAs to miR-21 increased luciferase reporter activity in construct plasmids containing the RECK-3'-UTR microRNA response elements MRE21-1, MRE21-2, and MRE21-3. The role of miR-21 in cell proliferation was also analyzed, and cancer cells transfected with siRNAs exhibited a markedly reduced cell proliferation and migration. Our findings indicate that miR-21 post-transcriptionally down-regulates the expression of RECK to promote cell proliferation and cell migration inhibition in cervical cancer cell survival. Therefore, miR-21 and RECK may be potential therapeutic targets in gene therapy for cervical cancer.

Unmasking the Hypoxia Landscape in Cervical Cancer: S100A2 and Its Implication for Immunotherapy Resistance

Cervical cancer is the fourth most common cancer in women worldwide and typically diagnosed between the ages of 35 and 44. Despite the death rate declining 1% each year since the 2000s, the 5-year survival of late stage remains lower than 20%. This emphasizes the urgency to keep exploring cervical cancer cell survival factors and identifying new prognostic markers. In this issue of Reproductive Sciences, Yang et al. stratified hypoxia subtype by analyzing 200 hypoxia-related genes in TCGA database and observed patient overall survival, hypoxic, transcriptome, genomics, and immunological characteristics vary among these hypoxia subtypes and created a hypoxia score which successfully stratified patient by predicting clinical outcomes and response to immunotherapy. Simultaneously, a hypoxia mediator (S100A2) associated with an aggressive cervical cancer phenotype is identified. We reviewed similar work on S100A2 and hypoxia-mediated multidrug resistance and highlighted the values added by this study. Future work could focus on unraveling the direct link between S100A2 and immunotherapy resistance.

Pharmacophore based virtual screening for identification of effective inhibitors to combat HPV 16 E6 driven cervical cancer

Targeting HPV16 E6 has emerged as an effective drug target for the treatment/management of cervical cancer. We utilized pharmacophore-based virtual screening, molecular docking, absorption, distribution, metabolism and excretion (ADME) prediction, and molecular dynamics simulation approach for identifying potential inhibitors of HPV16 E6. Initially, we generated a ligand-based pharmacophore model based on the features of four known HPV16 E6 inhibitors (CA24, CA25, CA26, and CA27) via the PHASE module implanted in the Schrödinger suite. We constructed four-point pharmacophore features viz., three hydrogen bond acceptors (A) and one aromatic ring (R). The common pharmacophore feature further employed as a query for virtual screening against the ASINEX database via Schrödinger suite. The pharmacophore-based virtual screening filtered out top 2000 hits, based on the fitness score. We then applied the high throughput virtual screening (HTVS), standard precision (SP) and extra precision (XP). 1000 compounds were obtained from HTVS docking. Based on the glide score, they were further filtered to 500 hits by employing docking in standard precision mode. Finally, the best four hits and a negative molecule were identified using docking in XP mode. The four lead compounds and a negative molecule were then further subjected to ADME profile prediction by engaging Qikprop module. The ADME properties of the four lead molecules indicate good pharmacokinetic (PK) properties rather than the negative molecule. The binding stability of the HPV16 E6-hit complexes were investigated at a different time scale (100 ns) by using the desmond package and the results were examined using Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) and it revealed the stability of the protein-ligand complex throughout the simulation. Key residues, CYS 51 and GLN 107, also play a crucial role in enhancing the stability of the protein-ligand complex during the simulation. Furthermore, the binding free energy of the HPV16 E6-leads complexes was analyzed by prime which revealed that the ΔGbind coulomb and ΔGbind vdW interactions are crucially contributes to the binding affinity. In order to validate the computational findings, the efficacy of benzoimidazole and benzotriazole were ascertained for regulating ME180 cervical cancer cell survival, migration and ability to release MMP-2.

FNBP1 Facilitates Cervical Cancer Cell Survival by the Constitutive Activation of FAK/PI3K/AKT/mTOR Signaling.

Cervical cancer is the most prevalent gynecological tumor among women worldwide. Although the incidence and mortality of cervical cancer have been declining thanks to the wide-scale implementation of cytological screening, it remains a major challenge in clinical treatment. High viability is one of the leading causes of the chemotherapeutic resistance in cervical cancers. Formin-binding protein 1 (FNBP1) could stimulate F-actin polymerization beneath the curved plasma membrane in the cell migration and endocytosis, which had previously been well defined. Here, FNBP1 was also demonstrated to play a crucial role in cervical cancer cell survival, and the knockdown of which could result in the attenuation of FAK/PI3K/AKT signaling followed by significant apoptotic accumulation and proliferative inhibition. In addition, the epidermal growth factor (hrEGF) abrogated all the biological effects mediated by the silencing of FNBP1 except for the cell adhesion decrease. These findings indicated that FNBP1 plays a key role in maintaining the activity of focal adhesion kinase (FAK) by promoting cell adhesion. The activated FAK positively regulated downstream PI3K/AKT/mTOR signaling, which is responsible for cell survival. Promisingly, FNBP1 might be a potential target against cervical cancer in combination therapy.

Nuclear factor (erythroid-derived 2)-like 2 counter-regulates thymosin beta-4 expression and primary cilium formation for HeLa cervical cancer cell survival

We investigated the function of thymosin beta-4 (TB4) expression and primary cilium (PC) formation via the underlying Nrf2-dependent mechanism for cervical cancer cell (CC) survival under conditions of serum deprivation (SD). TB4 silencing was achieved using RNA interference. The percentage of PC formation was analyzed by immunofluorescence staining. Nrf2 expression was modified by the preparation of stable Nrf2-knockdown cells with shNrf2 and the overexpression of Nrf2 with pcDNA-Nrf2 plasmids. Gene expression was measured using reverse-transcription PCR, Gaussia luciferase assay, and western blotting. Cell viability was assessed using the MTT assay or CellTiter Glo assay. Reactive oxygen species (ROS) were detected with flow cytometry. CCs incubated in SD without fetal bovine serum remained viable, and SD increased PC formation and TB4 transcription. CC viability was further decreased by treatment with ciliobrevin A to inhibit PC formation or TB4-siRNA. SD increased ROS, including H2O2. N-acetylcysteine inhibited ROS production following H2O2 treatment or SD, which also decreased PC formation and TB4 transcription. Meanwhile, H2O2 increased PC formation, which was attenuated in response to TB4 siRNA. Treatment with H2O2 increased Nrf2 expression, antioxidant responsive element (ARE) activity, and PC formation, which were inhibited by the Nrf2 inhibitor clobestasol propionate. Nrf2 knockdown via expression of Tet-On shNrf2 enhanced ROS production, leading to increased PC formation and decreased TB4 expression; these effects were counteracted by Nrf2 overexpression. Our data demonstrate that Nrf2 counter-regulates TB4 expression and PC formation for CC survival under conditions of SD, suggesting cervical CC survival could be upregulated by PC formation via Nrf2 activation and TB4 expression.

Morphine stimulates cervical cancer cells and alleviates cytotoxicity of chemotherapeutic drugs via opioid receptor-dependent and -independent mechanisms.

Morphine is frequently applied in cancer patients for pain management. However, its effects on cancer are not well understood but observed to be specific to certain cancer types. We previously revealed the stimulatory properties of morphine in esophageal carcinoma. This work addressed the effects of morphine and its underlying mechanisms in cervical cancer. Proliferation, apoptosis, and migration assays were performed to examine the effects of morphine alone and its combinatory effects with chemotherapeutic drugs. Immunoblotting and biochemical analysis were performed to determine the underlying mechanisms of morphine's action. Morphine promoted proliferation in opioid receptor‐dependent manner and stimulated migration in opioid receptor‐independent manner. However, morphine did not affect cervical cancer cell survival. Morphine also interfered with all tested chemotherapeutic drugs (e.g., cisplatin, 5‐FU, and paclitaxel) and alleviates their efficacy. Mechanistically, morphine‐stimulated growth via activating EGFR‐mediated signaling pathways and is opioid‐receptor‐dependent; morphine‐stimulated migration via activating RhoA‐mediated signaling pathways and this is opioid receptor‐independent. Our work suggests a strong correlation of this opioid receptor on growth factor signaling to stimulate growth and opioid receptor‐independent activation of RhoA and consequent migration. Our findings have the potential to guide the clinical use of morphine for patients with cervical cancer.

Methanolic neem (Azadirachta indica) stem bark extract induces cell cycle arrest, apoptosis and inhibits the migration of cervical cancer cells in vitro

BackgroundCervical cancer remains one of the significant causes of mortality in women due to the limitations of current treatment strategies and their associated side effects. Investigation of alternative medicine, including phytomedicine, has shown effective anti-cancer potential with fewer side effects. Azadirachta indica (commonly known as neem) is known for its medicinal properties. The present study investigated the anti-cancer potential of methanolic neem stem bark extract (MNBE) against cervical cancer using HeLa, SiHa, and ME-180 cell lines.MethodsCytotoxic effect of MNBE on cultured cell lines was evaluated by MTT and clonogenic assay. The growth-inhibiting effect of MNBE was further confirmed by performing cell cycle analysis and apoptosis assay using flow cytometry. The anti-migratory effect of MNBE was evaluated by using wound healing and Boyden chamber assay. Real-time PCR was used to determine the mRNA expression, and western blot and flow cytometry was used to determine the protein levels of growth and migration-related genes.ResultsMNBE significantly suppressed the growth and survival of cervical cancer cells in a dose-dependent manner by inducing cell cycle arrest and apoptosis. In addition, the growth inhibitory effect of MNBE was specific to cervical cancer cells than normal cells. Cell cycle arrest was correlated to transcriptional downregulation of cyclin dependent kinase 1 (CDK1), cyclin A, and cyclin B. Additionally, MNBE treatment resulted in the upregulation of active caspase-3 protein and downregulation of prosurvival genes, Bcl2, and survivin at mRNA level and NFkB-p65 at the protein level. Furthermore, MNBE inhibited the migration of cervical cancer cells accompanied by modulation of migration-related genes, including zona occludens-1 (ZO-1), matrix metalloproteinase 2 (MMP2), focal adhesion kinase (FAK), N-cadherin, snail, and E-cadherin.ConclusionIn summary, the present study provides the first evidence of MNBE in restricting cervical cancer cell growth and migration, which warrants further investigation for developing novel anti-cancer drugs.

SFN Enhanced the Radiosensitivity of Cervical Cancer Cells via Activating LATS2 and Blocking Rad51/MDC1 Recruitment to DNA Damage Site.

Simple SummaryRadiotherapy is the main treatment for cervical cancer patients in advanced stages. However a considerable number of patients are not sensitive to radiotherapy. Dysregulation of DNA double-strand break (DSB) repair is characteristic of cancer cells in a radiotherapy-resistance state. The aim of this study is to explore Sulforaphane (SFN) downstream target and the radiotherapy sensitization mechanism in cervical cancer. We identified SFN as cervical cancer cells radiotherapy sensitizer and LATS2 served as a downstream target of SFN treatment. SFN treatment resulted in the inhibition of the homologous recombination (HR) pathway, and LATS2 has an indispensable contribution to this SFN-facilitated radiotherapy sensitization.Background: Sulforaphane (SFN) is one kind of phytochemical anticancer drug. It inhibits cancer cell proliferation and promotes cell apoptosis while the mechanism behind is still uncertain. We aimed to explore its downstream target and the radiotherapy sensitization mechanism in cervical cancer. Methods: We treated established cervical cancer cells line (SiHa, HeLa, C33A) with SFN followed by irradiation, and explored its survival, apoptosis, and DNA damage repair in vitro and validated the radiosensitivity of SFN treatment in vivo. We conducted mRNA sequencing to identify differentially expressed mRNAs after SFN treatment. We further investigated SFN downstream target and its involvement in DNA damage repair under irradiation. Results: We found that SFN inhibited the survival of cervical cancer cells under radiotherapy treatment in vitro and prolonged the survival period after radiotherapy in the mouse tumorigenic model. SFN increased the protein expression of LATS2 and promoted apoptosis of cervical cancer cells. Overexpressed LATS2 decreased the cellular survival rate of cervical cancer cells. Additionally, SFN treatment and LATS2 overexpression prevented MDC1 and Rad51 from accumulating in the nucleus in cervical cancer cells after being exposed to ionized radiation. LATS2 loss intervened with SFN-alleviated RAD51 and MDC1 nucleus accumulation and resumed the repairment of DNA damage. Conclusion: We identified SFN as cervical cancer cells radiotherapy sensitizer and LATS2 served as a downstream target of SFN treatment. SFN treatment resulted in the inhibition of the homologous recombination (HR) pathway, and LATS2 has an indispensable contribution to this SFN-facilitated radiotherapy sensitization.

Promotion of Cervical Cancer Cell Proliferation by miR-130b Expression Level Changes and Inhibition of its Apoptosis by Targeting CDKN1A Gene.

Background: Dysregulation of miR-130b expression is associated with the development of different cancers. However, the description of the biological roles of miR-130b in the growth and survival of cervical cancer cells is limited. Methods: The miR-130b levels in cervical cancer cells during different stages of growth were determined using reverse transcription-quantitative PCR. The methylation level of DNA sequences upstream of the miR-130b gene was measured using an SYBR Green-based quantitative methylation-specific PCR. Reverse transcription-quantitative PCR, Western blotting, and fluorescence report assays were used to identify the miR-130b-targeted gene. Cell counting kit-8 and comet assays were used to determine cell viability and DNA damage levels in cells, respectively. EdU Apopllo488 in vitro Flow Cytometry kit, propidium iodide staining, anti-γ-H2AX antibody staining, and Annexin-V apoptosis kit were subsequently used to determine DNA synthesis rates, cell cycle distribution, count of DNA double-strand breaks, and levels of apoptotic cells. Results: miR-130b levels increased at exponential phases of the growth of cervical cancer cells but reduced at stationary phases. The methylation of a prominent CpG island near the transcript start site suppressed the miR-130b gene expression. MiR-130b increased cell viability, promoted both DNA synthesis and G1 to S phase transition of the cells at exponential phases, but reduced cell viability accompanied by accumulations of DNA breaks and augmentations in apoptosis rates of the cells in stationary phases by targeting cyclin-dependent kinase inhibitor 1A mRNA. Conclusion: miR-130b promoted the growth of cervical cancer cells during the exponential phase, whereas it impaired the survival of cells during stationary phases.

Tissue-specific Physical and Biological Microenvironments Modulate the Behavior of Cervical Squamous Cell Carcinoma.

The mechanisms controlling the aggressiveness and survival of cervical SCC cells remain unclear. We investigated how the physical and biological microenvironments regulate the growth, apoptosis and invasiveness of cervical cancer cells. Dynamic flow and air exposure were evaluated as physical microenvironmental factors, and stromal fibroblasts were evaluated as a biological microenvironmental factor. To investigate any regulatory effects of these microenvironmental factors, we established a new culture model which concurrently replicates fluid streaming, air exposure and cancer-stromal interactions. Three cervical cancer cell lines were cultured with or without NIH 3T3 fibroblasts. Air exposure was realized using a double-dish culture system. Dynamic flow was created using a rotary shaker. Dynamic flow and air exposure promoted the proliferative activity and decreased the apoptosis of cervical cancer cells. Fibroblasts regulated the invasive ability, growth and apoptosis of cervical cancer cells. Extracellular signal-regulated kinase and p38 signaling were regulated either synergistically or independently by dynamic flow, air exposure and cellular interactions, depending on the cervical cancer cell type. This study demonstrates that the physical and biological microenvironments interact to regulate the aggressiveness and survival of cervical cancer cells. Our simple culture system is a promising model for developing further treatment strategies for various types of cancer.

DCLK1 might be a therapeutic target of osthole against cervical cancer.

Discovering compounds with anti-cervical cancer effect and clarifying their targets will help promoting the precise treatment of cervical cancer. The present study intended to clarify the effect of osthole on cervical cancer cells, and to explore the possibility of DCLK1 as its target. Annexin V-PE staining and flow cytometry methods were used to determine cell apoptosis. Meanwhile, apoptosis related biomarkers were probed by immunoblotting. The MTT assay was employed to study the effect of osthole in combined with or without LRRK2-IN-1 (a DCLK1 inhibitor) on cell proliferation. Then, combination index was determined. To examine the interaction of osthole with DCLK1, molecular docking was carried out. Based on the biological database from cBioPortal, the association between DCLK1 and clinical manifestations of cervical cancer were evaluated. The results showed that osthole can significantly induce apoptosis of HeLa and Me-180. When combined with LRRK2-IN-1, the effect of osthole on cell proliferation was antagonized, suggesting that it might competitive binding to DCLK1. Furthermore, molecular docking showed that osthole interacts with Val468 residues of DCLK1 to form hydrogen bonds. The analysis of database showed that DCLK1 frequently mutant and deleted in cervical cancer, and is related to cell survival, tumor progression and recurrence. However, no obvious correlations were found between DCLK1 and lymphatic metastasis/differentiation. In conclusion, osthole significantly inhibits the survival of cervical cancer cells. It's probably target DCLK1 mechanistically via interacting with Val468. DCLK1 could be a potential therapeutic target for cervical cancer.

PTEN downregulation induces apoptosis and cell cycle arrest in uterine cervical cancer cells.

The tumor suppressors PTEN and p53 are often downregulated in various human cancer types, which has been associated with a poor prognosis. Recent evidence implies that PTEN downregulation may induce growth arrest of kidney cells and cancer cells. In the present study, the role of PTEN in the proliferation and survival of cervical cancer cells was investigated. It was found that PTEN silencing promoted apoptosis and cell-cycle arrest, accompanied by a significant decrease in the proportion of cells in the S1 phase of the cell cycle. Moreover, PTEN silencing in cervical cancer cells increased levels of p53, p27, p21, phospho-ERK and cleaved caspase-3, and decreased levels of cyclin A2 and cyclin D1. Furthermore, PTEN knockdown significantly impacted the viability of cervical cancer cells. P53 silencing did not affect the ability of PTEN knockdown to induce apoptosis in cervical cancer cells. Taken together, the present study results imply that PTEN silencing induces apoptosis and decreases proliferation in cervical cancer cells; hence, PTEN inhibition may represent a promising strategy for the treatment of cervical cancer.

Essential Oil from Zingiber ottensii Induces Human Cervical Cancer Cell Apoptosis and Inhibits MAPK and PI3K/AKT Signaling Cascades.

Zingiber ottensii (ZO) is a local plant in Thailand and has been used as a Thai traditional therapy for many conditions. ZO has been reported to exhibit many pharmacological effects, including anti-cancer activity. Nevertheless, its anti-cancer effects explored at the signaling level have not been elucidated in cervical cancer, which is one of the leading causes of fatality in females. We discovered that the essential oil of ZO significantly increased the apoptosis of human cervical cancer cells (HeLa) after 24 h of treatment in a concentration-dependent manner. Our data also clearly demonstrated that ZO essential oil reduced IL-6 levels in the culture supernatants of the cancer cells. Moreover, Western blot analysis clearly verified that cells were induced to undergo apoptotic death via caspase activation upon treatment with ZO essential oil. Interestingly, immunofluorescence studies and Western blot analyses showed that ZO essential oil suppressed epidermal growth factor (EGF)-induced pAkt and pERK1/2 signaling pathway activation. Together, our study demonstrates that ZO essential oil can reduce the proliferation and survival signaling of HeLa cervical cancer cells. Our study provides convincing data that ZO essential oil suppresses the growth and survival of cervical cancer cells, and it may be a potential choice for developing an anti-cancer agent for treating certain cervical cancers.

Msi1 inhibits cervical cancer cell apoptosis by downregulating BAK through AKT signaling.

Musashi-1 (Msi1) is an RNA binding protein that functions as a regulator in multiple carcinomas. Our previous study demonstrated that Msi1 could promote the proliferation of cervical cancer cells by targeting the cell cycle proteins P21, P27 and P53. However, the mechanisms by which Msi1 affects the survival of cervical cancer cells, such as apoptosis, are still unclear. In this study, we found that the expression of Msi1 inhibited cervical cancer cell apoptosis in vitro and in vivo. Furthermore, the expression of Msi1 downregulated the expression of PTEN, while AKT signaling was activated, which resulted in a reduction in the proapoptotic protein BAK. In addition, rescue the expression of BAK in Msi1 expressing cervical cancer cells induced the increase of apoptosis cells. These findings indicate that Msi1 regulates cervical cancer cell apoptosis by inhibiting PTEN and activating AKT signaling, which leads to the downregulation of BAK.

VPS50 is required for the proliferation and survival of cervical cancer cells

VPS50 is required for the proliferation and survival of cervical cancer cells

Inhibition Capacity of the n-Hexane Fraction of Myrmecodia pendens as a Potential Anti-Cancer in Breast and Cervical Cancer: In Vitro Study

Breast cancer (BC) and cervical cancer (CC) have a high prevalence and mortality rate worldwide. Despite the availability of advanced treatment, resistance to conventional chemotherapies has emerged. Myrmecodia pendens, one of the species of Sarang Semut (local name), possess a potential of antitumor effects by inducing cell death different cancer cell entities. This study aimed to assess anti-tumor activities of n-hexane fraction of M. pendens in inhibiting cell survival and cell migration in BC and CC cells. M. pendens was extracted in methanol then fractionated using n-hexane or ethyl acetate. BC cells including MCF-7 (luminal A), HCC-1954 (HER2+) cells and CC Hela cells were treated with M. pendens extracts to evaluate cytotoxic activity using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay as well as anti-cell migration using scratch assay. We also analyzed inhibitory concentration 50 (IC50) of n-hexane fraction in BC and CC cells. We started with comparing cytotoxicity activities of methanol extract, ethyl acetate and n-hexane fractions of M. pendens. Data showed that the n-hexane fraction was the most potent inducing BC cell death. Therefore, we used the n-hexane fraction for further experiments. Interestingly, IC50 of this fraction in HCC-1954 and Hela cells were lower than in MCF-7 cells, 16; 13 and 60 ppm, respectively. Moreover, the low concentrations of n-hexane fraction inhibited HeLa cells migration, compared to control group (p<0.05). The n-hexane fraction of M. pendens shows promising anti-cancer agent, by inhibiting BC and CC cell survival as well as inhibiting CC cells migration.Keywords: breast cancer, cervical cancer, MTT assay, Sarang Semut, scratch assay

Targeting mTOR by CZ415 Suppresses Cell Proliferation and Promotes Apoptosis via Lipin-1 in Cervical Cancer In Vitro and In Vivo.

CZ415, a novel inhibitor of mammalian target of rapamycin (mTOR) kinase, has demonstrated anti-tumor activity in several types of cancer. However, its biological function and underlying mechanism of action in cervical cancer (CC) have not beenfully studied. Two CC cell lines (Hela and Siha) were treated with increasing concentrations of CZ415. Cell viability was tested with the CCK-8 assay, cell proliferation was determined by Edu staining and the colony formation assay, and apoptosis was determined by flow cytometry and Hoechst 33342 staining. Protein expression was evaluated by western blotting. A nude mouse xenograft model was used to confirm the anti-tumor activity of CZ415 in vivo. Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining were performed on samples of tumor tissue. Results showed that CZ415 inhibited CC cell survival in a dose- and time-dependent manner, and 100 nanomolar and 48h were the optimal conditions. In vitro and in vivo experiments showed that treatment with CZ415 significantly inhibited spheroid formation, cell proliferation, and tumor growth. Further studies showed that the anti-cancer effects of CZ415 were due to an induction of apoptosis, which was accompanied by an upregulation of Bax and downregulation of Bcl-2through Lipin-1. CZ415 also reduced the levels of mTOR/STAT3 expression. However, these phenotypic changes were reversed by overexpression of Lipin-1. Our results suggest that the novel mTOR inhibitor CZ415 mediates tumor malignancy via Lipin-1 and might be useful for treating CC.

Targeting the B-cell lymphoma 2 anti-apoptotic proteins for cervical cancer treatment.

The B-cell lymphoma 2 (BCL-2) anti-apoptotic proteins have become attractive therapeutic targets especially with the development of BH3-mimetics which selectively target these proteins. However, it is important to note that expression levels of the anti-apoptotic proteins and their relevance in inhibiting apoptosis varies between different cell lineages. This addiction to certain anti-apoptotic proteins for survival, can be determined with various techniques and targeted effectively with selective BH3-mimetics. Studies have highlighted that anti-apoptotic proteins BCL-XL and MCL-1 are crucial for cervical cancer cell survival. Co-targeting BCL-XL and MCL-1 with selective BH3-mimetics yielded promising results in cervical cancer cell lines. In this review, we focus on the expression levels of the anti-apoptotic proteins in cervical cancer tissues and how to possibly target them with BH3-mimetics.

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

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.

Eriodictyol Suppresses Survival of Cervical Cancer Cells Through Mediation of PTEN/Akt Signaling Pathway

Cervical cancer is one of the most malignant cancers of the female reproductive system with high morbidity and mortality. In the current study, we have examined the effect of eriodictyol on cell survival including cell growth, cell cycle and apoptosis of cervical cancer cells and also explored the underlying mechanism(s). To this end, CCK-8 assay, flow cytometry and western blotting assays were performed in cervical cancer HeLa cells. Eriodictyol significantly inhibited cell survival including impeding the cell viability, arresting the cell cycle at the G1 phase and potentiating cell apoptosis in a concentration-dependent manner. Also, ERI activated PTEN, P21, cleaved caspase-3/-9 expression and downregulated P-Akt and cyclin D1 expression in a dose-dependent manner. In conclusion, ERI can inhibit cervical cancer HeLa cells viability via impeding cell cycle and inducing apoptosis by regulating PTEN/Akt signaling pathway.