Apoptosis In Cervical Cancer Cells Research Articles

Cisplatin-encapsulated TRAIL-engineered exosomes from human chorion-derived MSCs for targeted cervical cancer therapy

BackgroundCisplatin (DDP) is an efficacious and widely applied chemotherapeutic drug for cervical cancer patients who are diagnosed as metastatic and inoperable, or desiring fertility preservation. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) selectively triggers cancer cells apoptosis by binding to cognate death receptors (DR4 and DR5). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been regarded as ideal drug carriers on account of their nanoscale, low toxicity, low immunogenicity, high stability, biodegradability, and abundant sources.MethodsHuman chorion-derived mesenchymal stem cells (hCD-MSCs) were isolated by adherent culture method. TRAIL-engineered hCD-MSCs (hCD-MSCsTRAIL) were constructed by lentivirus transfection, and its secreted Exo (hCD-MSCs-ExoTRAIL) were acquired by differential centrifugation and confirmed to overexpress TRAIL by western blotting. Next, nanoscale drug delivery systems (DDP & hCD-MSCs-ExoTRAIL) were fabricated by loading DDP into hCD-MSCs-ExoTRAIL via electroporation. The CCK-8 assay and flow cytometry were conducted to explore the proliferation and apoptosis of cervical cancer cells (SiHa and HeLa), respectively. Cervical cancer-bearing nude mice were constructed to examine the antitumor activity and biosafety of DDP & hCD-MSCs-ExoTRAIL in vivo.ResultsCompared with hCD-MSCs-Exo, hCD-MSCs-ExoTRAIL weakened proliferation and enhanced apoptosis of cervical cancer cells. DDP & hCD-MSCs-ExoTRAIL were proved to retard cervical cancer cell proliferation and propel cell apoptosis more effectively than DDP or hCD-MSCs-ExoTRAIL alone in vitro. In cervical cancer-bearing mice, DDP & hCD-MSCs-ExoTRAIL evidently hampered tumor growth, and its role in inducing apoptosis was mechanistically associated with JNK/p-c-Jun activation and survivin suppression. Moreover, DDP & hCD-MSCs-ExoTRAIL showed favorable biosafety in vivo.ConclusionsDDP & hCD-MSCs-ExoTRAIL nanoparticles exhibited great promise for cervical cancer treatment as an Exo-based chemo-gene combinational therapy in clinical practice.Graphical abstract

RecQ protein-like 4 drives cisplatin chemosensitivity of cervical cancer cells by modulating annexin A2.

Cervical cancer is a common malignant tumor in women with high morbidity and mortality. Chemotherapy drugs such as cisplatin (DDP) are easy to cause chemotherapy resistance and affect the therapeutic effect. Hence, it is critical to design new therapies that can reverse chemotherapy resistance and increase sensitivity to chemotherapy drugs. This study investigated the function of RecQ protein-like 4 (RECQL4) in DDP-resistant cervical cancer cells and its regulatory mechanism. By constructing DDP-resistant Hela and CaSki cell lines, it was found that RECQL4 expression was elevated. RECQL4 knockdown is able to promote apoptosis, DNA damage, and increase the DDP sensitivity in cervical cancer cells. In vivo experiments have demonstrated that knockdown of RECQL4 suppresses tumor growth and promotes tumor apoptosis. Next, we investigated the potential regulatory relationship of RECQL4 to Annexin A2 (ANXA2). The results demonstrated that RECQL4 binds to ANXA2. Knockdown of RECQL4 downregulates the ANXA2 expression via promoting ubiquitination. Furthermore, we also found that ANXA2 overexpression partially abolished the role of RECQL4 knockdown in promoting apoptosis and DNA damage of cervical cancer cells, suggesting that RECQL4 plays a role in DDP sensitivity of cervical cancer cells by mediating ANXA2. In conclusion, the present study suggests that knocking down RECQL4 reduces DDP sensitivity in cervical cancer cells by modulating ANXA2. Targeting RECQL4 therapy may be a new strategy to improve chemosensitivity of cervical cancer cells.

Susceptibility of HPV-18 Cancer Cells to HIV Protease Inhibitors.

Cervical cancer cases continue to rise despite all the advanced screening and preventative measures put in place, which include human papillomavirus (HPV) vaccination. These soaring numbers can be attributed to the lack of effective anticancer drugs against cervical cancer; thus, repurposing the human immunodeficiency virus protease inhibitors is an attractive innovation. Therefore, this work was aimed at evaluating the potential anticancer activities of HIV-PIs against cervical cancer cells. The MTT viability assay was used to evaluate the effect of HIV protease inhibitors on the viability of cervical cancer cells (HeLa) and non-cancerous cells (HEK-293). Further confirmation of the MTT assay was performed by confirming the IC50s of these HIV protease inhibitors on cervical cancer cells and non-cancerous cells using the Muse™ Count and Viability assay. To confirm the mode of death induced by HIV protease inhibitors in the HPV-associated cervical cancer cell line, apoptosis was performed using Annexin V assay. In addition, the Muse™ Cell Cycle assay was used to check whether the HIV protease inhibitors promote or halt cell cycle progression in cervical cancer cells. HIV protease inhibitors did not affect the viability of non-cancerous cells (HEK-293), but they decreased the viability of HeLa cervical cancer cells in a dose-dependent manner. HIV protease inhibitors induced apoptosis in HPV-related cervical cancer cells. Furthermore, they also induced cell cycle arrest, thus halting cell cycle progression. Therefore, the use of HIV drugs, particularly HIV-1 protease inhibitors, as potential cancer therapeutics represents a promising strategy. This is supported by our study demonstrating their anticancer properties, notably in HPV-associated cervical cancer cell line.

Pulsed electromagnetic fields inhibit IL-37 to alleviate CD8+ T cell dysfunction and suppress cervical cancer progression.

Pulsed electromagnetic field (PEMF) therapy is a potential non-invasive treatment to modulate immune responses and inhibit tumor growth. Cervical cancer (CC) is influenced by IL-37-mediated immune regulation, making PEMF therapy a potential strategy to impede CC progression. This study aimed to elucidate the effects of PEMF on IL-37 regulation and its molecular mechanisms in CC. CC cell-xenografted mouse models, including IL-37 transgenic (IL-37tg) mice, were used to assess tumor growth through in vivo fluorescence imaging and analyze CC cell apoptosis via flow cytometry. TCGA-CESC transcriptome and clinical data were analyzed to identify key inflammation and immune-related genes. CD8+ T cell models were stimulated with PEMF, and apoptosis, oxidative stress, and inflammatory factor expression were analyzed through RT-qPCR, Western blot, and flow cytometry. PEMF treatment significantly inhibited IL-37 expression (p < 0.05), promoted inflammatory factor release (TNF-α and IL-6), and activated oxidative stress, leading to increased CC cell apoptosis (p < 0.05). IL-37 interaction with SMAD3 impacted the p38/NF-κB signaling pathway, modulating CD8+ T cell activity and cytotoxicity. Co-culture of Hela cells with CD8+ T cells under PEMF treatment showed reduced proliferation (by 40%), migration, and invasion (p < 0.05). In vivo experiments with CC-bearing mice demonstrated that PEMF treatment downregulated IL-37 expression (p < 0.05), enhanced CD8+ T cell function, and inhibited tumor growth (p < 0.05). These molecular mechanisms were validated through RT-qPCR, Western blot, and immunohistochemistry. Thus, PEMF therapy inhibits CC progression by downregulating IL-37 and improving CD8+ T cell function via the SMAD3/p38/NF-κB signaling pathway.

KLF14 directly downregulates the expression of GPX4 to exert antitumor effects by promoting ferroptosis in cervical cancer

BackgroundCervical cancer is the fourth leading cause of cancer-related death among women worldwide, and effective therapeutic strategies for its treatment are limited. Recent studies have indicated that ferroptosis, a form of regulated cell death, is a promising therapeutic strategy. KLF14 has been shown to regulate both cell proliferation and apoptosis in cervical cancer. However, its role in modulating lipid peroxidation and ferroptosis remains largely unexplored and enigmatic.MethodsSiHa and HeLa cells were transduced with lentiviral vectors to overexpress KLF14. Protein levels were analyzed via western blotting and immunohistochemistry (IHC). LDH assays, calcein-AM/propidium iodide (PI) staining, and generation of cell growth curves using a real-time cell analysis (RTCA) system were used to detect cell damage and proliferation. Cellular ROS, lipid ROS, transmission electron microscopy (TEM), and Fe2+ assays and a xenograft mouse model were used to measure the level of ferroptosis. Proteomics combined with bioinformatics methods was used to screen target genes regulated by KLF14, and CUT&Tag and dual-luciferase assays confirmed the repression of GPX4 by KLF14 via direct binding to its promoter.ResultsKLF14 is abnormally expressed in various tumors and downregulated in cervical cancer. Overexpression of KLF14 induced ferroptosis and inhibited cell proliferation in vitro as well as xenograft tumorigenicity in vivo. Mechanistic studies revealed that KLF14 binds to the promoter of GPX4, suppressing its transcriptional activity and thereby decreasing its expression, which contributes to the induction of ferroptosis. Truncation and point mutation analyses of the GPX4 promoter revealed multiple binding sites for KLF14 within the − 1000 bp to + 35 bp region, which are responsible for its inhibitory effect on GPX4 transcription. Additionally, deletion of the zinc finger motif in KLF14 abolished its inhibitory effect on GPX4 promoter activity and cell proliferation.ConclusionOur data revealed a previously unidentified function of KLF14 in promoting ferroptosis, which results in the suppression of cell proliferation. Mechanistically, we revealed a novel regulatory mechanism by which KLF14 targets GPX4. These findings suggest a novel strategy to induce ferroptosis through the targeting of KLF14 in human cervical cancer cells.

MCPIP1 Elicits a Therapeutic Effect on Cervical Cancer by Facilitating XIAP mRNA Decay via Its Endoribonuclease Activity.

Cervical cancer is the fourth most common malignancy in women globally. Chemotherapies, targeted therapies, and immunotherapies in the treatment of cervical cancer are usually accompanied by effective and adverse effects. Therefore, finding other efficient and accurate molecular targets remains essential to improve the treatment benefits of cervical cancer patients. MCPIP1 (monocyte chemoattractant protein-induced protein 1) is a kind of endonuclease with a CCCH zinc finger domain and a PilT-N-terminal (PIN) domain, and its function in cervical cancer is unknown. We found that MCPIP1 inhibits cell proliferation and promotes cell apoptosis of cervical cancer. Additionally, MCPIP1 suppresses mRNA and protein expression of the apoptotic inhibitor XIAP by decreasing its mRNA stability. Mechanically, MCPIP1 binds to the XIAP mRNA via its CCCH zinc finger domain and degrades the XIAP mRNA via the endonuclease activity coming from its PIN domain. Our study clarifies that MCPIP1 promotes cervical cancer cell apoptosis by suppressing the expression of XIAP, thereby impeding cervical cancer progression. Moreover, targeted delivery of MCPIP1 with engineered Salmonella typhimurium leads to tumor growth retardation in the HeLa xenograft tumor model in mice. Therefore, our study may provide a theoretical basis for formulating clinical treatment strategies for cervical cancer.

Urdamycin V from Streptomyces sp induces p53 independent apoptosis in cervical cancer cells inconsiderate of HPV status and inhibited growth of gram-positive human pathogens

In cervical cancer, loss of p53 or mutant non-functional p53 and hyperactivated mTOR/Akt pathway positively correlates to cancer progression. Urdamycin V isolated from Streptomyces OA293 is a recently isolated novel angucycline derivative that in the present study showcased induction of p53 independent apoptosis in both HPV (Human papillomavirus) positive and negative cervical cancer cell lines. Apoptosis induction was via phosphorylation modulation in the cell growth regulating proteins along mTORC2/Akt/p38/Erk pathway. The compound was also tested against human pathogens and selectively inhibited gram-positive strains, Streptococcus pyogenes and Staphylococcus aureus. The present study put forward urdamycins as a potential therapeutic that places promise for further research.

RNF113A as a poor prognostic factor promotes metastasis and invasion of cervical cancer through miR197/PRP19/P38MAPK signaling pathway

It has been discovered that aberrant expression of RNF113A plays a significant role in various diseases, including esophageal cancer, hepatocellular carcinoma, and X-linked trichothiodystrophy syndrome. Nevertheless, its functional implications in cervical cancer (CC) remain unclear. The objective of this study was to investigate the role of RNF113A in both the development and prognosis of CC. To achieve this objective, a total of sixty cases were included in the follow-up investigation. The findings revealed a significant up-regulation of RNF113A protein in CC tissues compared to paired paracancerous tissues, and a high expression level of RNF113A was strongly associated with malignant phenotypes such as lymph node metastasis, differentiation degree, depth of invasion, and FIGO stage. Meanwhile, RNF113A was found to be an independent prognostic risk factor, with its high expression significantly correlating with a reduced overall survival period in patients. To elucidate the underlying cause and mechanism of the unfavorable prognosis associated with RNF113A, comprehensive functional investigations were conducted both in vitro and in vivo.Interestingly, it was revealed that RNF113A promoted migration and invasion while inhibiting apoptosis of CC cells, thereby contributing to a poor prognosis. Mechanistically, RNF113A regulated the progression and prognosis of CC through the miR197/Prp19/p38Mark signaling pathway. Overall, our findings underscore the potential clinical significance of RNF113A as an unfavorable prognostic factor in CC.

Activating Transcription Factor 5; A Potential Prognostic Molecular Biomarker for Cervical Cancer (CC)

Background: Prognostic biomarkers with high sensitivity and specificity that accurately predict disease prognosis are crucial for influencing cancer patients' treatment and disease progression choices. This research attempts to determine ATF5's cervical cancer prognostic value and find a theoretical basis for cervical cancer treatment. Method: This study began with a survival analysis, then univariate and multivariate analyses using transcriptomics, methylation, and TCGA ATF5 clinical data. Second, ATF5's role in cervical cancer development was explored using GO, KEGG, and TIMER databases. We assessed ATF5's cervical cancer treatment potential using CMap, a drug development tool. Results: After conducting several analyses, we discovered that high levels of ATF5 mRNA expression and low levels of methylation were beneficial for patients with cervical cancer prognosis. An important finding is that ATF5 may promote apoptosis in cervical carcinoma cells. In addition, we assessed the therapeutic potential of four small molecules against cervical cancer. ATF 5 function as a tumor suppressor gene in cervical cancer has been demonstrated for the first time using numerous databases and bioinformatics techniques from multiple dimensions, which is a novel aspect of this research. Moreover, the finding that ATF5 is a biomarker that can contribute to the apoptosis of cervical cancer cells and predict a favorable prognosis for the disease was an additional innovation. In the future, ATF5 can be used as a therapeutic target and to develop anti-cancer medications.

Splicing Factor PTBP1 Silencing Induces Apoptosis of Human Cervical Cancer Cells via PI3K/AKT Pathway and Autophagy.

Cervical cancer is the most common gynecological malignancy in the world and seriously threatens to women's lives and health. Polypyrimidine tract binding protein 1 (PTBP1), as an important splicing factor, has been identified as a proto-oncogene in several cancers, but its role and mechanism in cervical cancer remain poorly understood. Thus, our aim is to explore the impact of PTBP1 on proliferation, migration, apoptosis of cervical cancer cells, and its underlying mechanisms. The biological functions in cervical cancer cells were determined using small interfering RNA (siRNA), agonist, Cell Counting Kit-8 (CCK-8), transwell, migration test, western blot, real-time-PCR, immunohistochemistry and immunofluorescence, respectively. The results indicated that PTBP1 was highly expressed in cervical cancer patients and cervical cancer cell lines compared to the normal group. Moreover, PTBP1 silencing significantly inhibited cell proliferation, and migration in both HeLa and SiHa cells. The PTBP1 silencing also induced mitochondrial apoptosis through upregulating Bax and mitochondrial apoptotic protein Cytochrome C, and downregulating B-Cell Leukemia/Lymphoma 2 (Bcl2) protein. Additionally, PTBP1 silencing induced autophagy by downregulating Sequestosome I (p62) and upregulating the ratio of Light chain 3-Ⅱ/Light chain 3-Ⅰ (LC3-Ⅱ/LC3-Ⅰ). Mechanistically, we found that the Phosphoinositide 3-kinase (PI3K) agonist reversed the changes induced by PTBP1 silencing. Overall, PTBP1 silencing can induce cervical cancer cells apoptosis mainly through PI3K/AKT pathway and protective autophagy. This study provides preliminary evidence for PTBP1 as a therapeutic target or prognostic marker for cervical cancer.

The closed loop of the circCLIP2/miR-361-3p/STAT2 signaling axis regulates the progression of cervical cancer

BackgroundCircular RNAs (circRNAs) are involved in tumorigenesis and the progression of cancer through various pathways. However, the detailed regulatory mechanisms of circRNAs in cervical cancer are not fully understood. The present study was designed to explore the biological functions and potential mechanisms of circCLIP2 (has_circ_0001717) in cervical cancer. MethodsThe expression profiles of circRNAs in cancerous and adjacent normal tissues of cervical cancer patients were examined using RNA sequencing. Gain- and loss-of-function experiments were carried out to determine the biological functions of circCLIP2 in the proliferation, invasion, migration and apoptosis of cervical cancer cells. qRT-PCR was also used to evaluate the expression of circCLIP2, miR-361-3p and STAT2 in cervical cancer cells. The protein levels of STAT2 were determined by western blotting. ResultsCircCLIP2 was identified as the most down-regulated molecule in the cancerous tissues of cervical cancer patients compared to the adjacent normal tissues. Moreover, the levels of circCLIP2 was decreased in cervical cancer patients with metastasis and advanced tumour stage, and patients with high-circCLIP2-expression exhibited poorer survival rate. In addition, over-expression of circCLIP2 suppressed the proliferation, invasion and migration of cervical cancer cells, whereas cell apoptosis was enhanced. Moreover, down-regulated circCLIP2 functioned as the sponge of miR-361-3p, which reduced the expression of STAT2. Furthermore, knockdown of STAT2 inhibited the expression of circCLIP2 at the transcriptional level. ConclusionThe circCLIP2/miR-361-3p/STAT2 signalling could mediate the progression of cervical cancer. CircCLIP2 may become a novel target for the diagnosis and treatment of cervical cancer.

Targeting MCL1 with Sanggenon C overcomes MCL1-driven adaptive chemoresistance via dysregulation of autophagy and endoplasmic reticulum stress in cervical cancer

BackgroundCervical cancer ranks as one of the most prevalent malignancies among women worldwide and poses a significant threat to health and quality of life. MCL1 is an antiapoptotic protein closely linked to tumorigenesis, drug-resistance and poor prognosis in various cancers. Sanggenon C, a natural flavonoid derived from Morus albal., exhibits multiple activities, including anti-oxidant, anti-inflammatory, antivirus, and antitumor properties. However, the molecular mechanisms by which Sanggenon C exerts antitumor effects on in cervical cancer remain unclear. PurposeTo investigate the oncogenic role of MCL1 and elucidate the antitumor activity of Sanggenon C, along with its molecular mechanisms, in cervical cancer. MethodsIn vitro, the effects of Sanggenon C on proliferation, the cell cycle, apoptosis, and autophagy were explored. Transcriptome sequencing was employed to analyze critical genes and pathways. The expression of genes or proteins was evaluated via immunofluorescence, qRT-PCR, immunohistochemistry, and Western blotting. To identify targets of Sanggenon C, various techniques such as clinical database analysis, molecular docking, cellular thermal shift assays, co-immunoprecipitation, and ubiquitination assays were utilized. Additionally, Xenograft mouse models were established to further investigate Sanggenon C as a novel MCL1 inhibitor and its anti-tumor activity in vivo. ResultsOur investigation reveals that Sanggenon C effectively inhibits cervical cancer cell proliferation both in vitro and in vivo. Furthermore, Sanggenon C induces endoplasmic reticulum stress and triggers protective autophagy via activation of the ATF4-DDIT3-TRIB3-AKT-MTOR signaling axis. Furthermore, Sanggenon C specifically targets MCL1 to exert its antitumor effects by modulating MCL1 protein stability through SYVN1-mediated ubiquitination. Notably, MCL1 overexpression attenuates the Sanggenon C-induced decrease in cell viability and apoptosis. Our study further characterizes the role of MCL1 in cisplatin resistance and identifies MCL1 as a promising target for Sanggenon C, which effectively inhibits proliferation and induces apoptosis in cisplatin-resistant cervical cancer cells. Importantly, combining Sanggenon C with an autophagy inhibitor represents a promising strategy to enhance therapeutic outcomes in cisplatin-resistant cervical cancer cells. ConclusionOur findings demonstrates that Sanggenon C induces endoplasmic reticulum stress and highlights the potential of targeting MCL1 to exploit vulnerabilities in drug-resistant cervical cancer cells. Sanggenon C emerges as a promising therapeutic agent against MCL1-driven adaptive chemoresistance through disruption of autophagy and endoplasmic reticulum stress in cervical cancer.

ZIP14 Affects the Proliferation, Apoptosis, and Migration of Cervical Cancer Cells by Regulating the P38 MAPK Pathway.

Cervical cancer (CC) remains a major public health concern and is a leading cause of female mortality worldwide. Understanding the molecular basis of its pathogenesis is essential for the development of novel therapeutic strategies. In this study, we aimed to dissect the role of a specific molecule, ZIP14, in the initiation and progression of CC. We used Gene Expression Omnibus for target gene identification, while KEGG was used to delineate CC-related pathways. Proliferation, migration, and apoptosis levels in CC cells were assessed using CCK8, Transwell, and flow cytometry, respectively. The effect of the target genes on the in vivo tumorigenesis of CC cells was evaluated using the subcutaneous tumorigenesis assay. ZIP14 (SLC39A14) was found to be underexpressed in CC samples. Our KEGG pathway analysis revealed the potential involvement of the P38 mitogen-activated protein kinase (MAPK) pathway in CC pathogenesis. Overexpression of ZIP14 in HeLa and Caski cells increased p38 phosphorylation, inhibited cell growth and migration, and enhanced apoptosis. Conversely, ZIP14 knockdown produced the opposite effects. Importantly, the bioeffects induced by ZIP14 overexpression could be counteracted by the p38 MAPK pathway inhibitor SB203580. In vivo experiments further confirmed the influence of ZIP14 on CC cell migration. Our study is the first to elucidate the pivotal role of ZIP14 in the pathogenesis of CC, revealing its inhibitory effects through the activation of the p38 MAPK signaling pathway. The discovery not only provides a deeper understanding of CC's molecular underpinnings, but also highlights ZIP14 as a promising therapeutic target. As ZIP14 holds significant potential for therapeutic interventions, our findings lay a robust foundation for further studies and pave the way for the exploration of novel treatment modalities for cervical cancer.

Ganoderic acid a derivative induces apoptosis of cervical cancer cells by inhibiting JNK pathway

ObjectiveGanoderic acid A can inhibit the proliferation and promotes the apoptosis of cancer cells. Surprisingly, the molecular mechanisms underlying the anti-cancer effects of ganoderic acid A still remain poorly defined. Ganoderic acid A derivative (GaAD19) is an effective ingredient obtained by structural modification of ganoderic acid A. The purpose of this study was to evaluate the anti-proliferation effect of GaAD19 on cervical cancer cells. MethodsThrough the HeLa cervical cancer cell model, the drug target of GaAD19 was predicted using the SwissTargetPrediction database and molecular docking. Subsequently, computer analysis results were verified by a series of molecular biology experiments, such as flow cytometry, Western blot, immunocytochemical staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), quantitative real time polymerase chain reaction (qPCR), and so on. Then, pathway agonists and inhibitors were used to investigate the mechanism of GaAD19. Finally, the mouse model of cervical cancer was established to evaluate the inhibitory effect of GaAD19 on tumor growth in U14 cervical cancer mice. ResultsGaAD19 induced apoptosis and inhibited the growth of tumors. It also blocked the transition from the G1 to the S phase of the cell cycle. However, in the presence of a c-Jun N-terminal kinase (JNK)agonist, the effects of GaAD19 on the proliferation, apoptosis, and cell cycle transition of cancer cells were suppressed. ConclusionsThis study showed that GaAD19 can play an anti-cervical cancer role by inhibiting the JNK signaling pathway. These results will be helpful in further exploring the mechanism of GaAD19 in the treatment of cervical cancer.

Dicerandrol C Suppresses Proliferation and Induces Apoptosis of HepG2 and Hela Cancer Cells by Inhibiting Wnt/β-Catenin Signaling Pathway.

Overwhelming evidence points to an aberrant Wnt/β-catenin signaling as a critical factor in hepatocellular carcinoma (HCC) and cervical cancer (CC) pathogenesis. Dicerandrol C (DD-9), a dimeric tetrahydroxanthenone isolated from the endophytic fungus Phomopsis asparagi DHS-48 obtained from mangrove plant Rhizophora mangle via chemical epigenetic manipulation of the culture, has demonstrated effective anti-tumor properties, with an obscure action mechanism. The objective of the current study was to explore the efficacy of DD-9 on HepG2 and HeLa cancer cells and its functional mechanism amid the Wnt/β catenin signaling cascade. Isolation of DD-9 was carried out using various column chromatographic methods, and its structure was elucidated with 1D NMR. The cytotoxicity of DD-9 on HepG2 and HeLa cells was observed with respect to the proliferation, clonality, migration, invasion, apoptosis, cell cycle, and Wnt/β-catenin signaling cascade. We found that DD-9 treatment significantly reduced tumor cell proliferation in dose- and time-dependent manners in HepG2 and HeLa cells. The subsequent experiments in vitro implied that DD-63 could significantly suppress the tumor clonality, metastases, and induced apoptosis, and that it arrested the cell cycle at the G0/G1 phase of HepG2 and HeLa cells. Dual luciferase assay, Western blot, and immunofluorescence assay showed that DD-9 could dose-dependently attenuate the Wnt/β-catenin signaling by inhibiting β-catenin transcriptional activity and abrogating β-catenin translocated to the nucleus; down-regulating the transcription level of β-catenin-stimulated Wnt target gene and the expression of related proteins including p-GSK3-β, β-catenin, LEF1, Axin1, c-Myc, and CyclinD1; and up-regulating GSK3-β expression, which indicates that DD-9 stabilized the β-catenin degradation complex, thereby inducing β-catenin degradation and inactivation of the Wnt/β-catenin pathway. The possible interaction between DD-9 and β-catenin and GSK3-β protein was further confirmed by molecular docking studies. Collectively, DD-9 may suppress proliferation and induce apoptosis of liver and cervical cancer cells, possibly at least in part via GSK3-β-mediated crosstalk with the Wnt/β-catenin signaling axis, providing insights into the mechanism for the potency of DD-9 on hepatocellular and cervical cancer.

Artesunate promotes cervical cancer cell apoptosis by regulating Bcl2 family molecules and reducing the mitochondrial membrane potential.

Artesunate (ART), an antimalarial drug, has a broad spectrum of antitumour effects in cancer types such as esophageal and gastric cancer. However, evidence demonstrating the role of ART in cervical cancer cells is limited. In the present study, the inhibitory effect of ART on the growth of cervical cancer cells through the modulation of the cell cycle and apoptosis was investigated. The growth-inhibitory effect of ART on a cervical cancer cell line (SiHa) was detected using a Cell Counting Kit-8 assay after treatment with ART for 24 h, after which the half-maximal inhibitory concentration (IC50) was calculated. Using flow cytometry assays, apoptosis, the cell cycle, the levels of reactive oxygen species (ROS) and calcium (Ca2+) ions, as well as the mitochondrial membrane potential were evaluated in SiHa cells following treatment with ART for 24 and 48 h. The mRNA expression levels of Bcl2, Bcl-xl, (myeloid cell leukaemia 1) Mcl-1, Bcl2-like protein 11 (BIM), (Bcl2-related ovarian killer protein) Bok, Bax and (Bcl2 homologous antagonist/killer) Bak in SiHa cells were detected using reverse transcription-quantitative PCR. ART inhibited the growth of SiHa cells in a dose-dependent manner. The IC50 of ART in SiHa cells was 26.32 µg/ml. According to the IC50 value, 15, 30 and 100 µg/ml ART were selected for further experiments, and normal saline (0 µg/ml ART) was used as the control group. The results indicated that treatment with 15, 30 and 100 µg/ml ART for 24 and 48 h induced apoptosis, increased the levels of ROS, the levels of Ca2+ and the mRNA expression levels of BIM, Bok, Bax and Bak, but decreased the cell proliferation indices, the mitochondrial membrane potential and the mRNA expression levels of Bcl2, Bcl-xl and Mcl-1 in a dose- and time-dependent manner. In conclusion, ART inhibited the growth of SiHa cells and induced apoptosis via a mechanism associated with the regulation of Bcl2 family member expression, which was associated with the increase of the levels of ROS and Ca2+ and the reduction of the mitochondrial membrane potential.

MicroRNA-875-5p inhibits the growth and metastasis of cervical cancer cells by promoting autophagy and apoptosis and inhibiting the epithelial-mesenchymal transition.

MicroRNA-875-5p (miR-875-5p) is a cancer-related microRNA. It has been demonstrated that miR-875-5p participates in the development of various types of cancer such as hepatocellular carcinoma, gastric carcinoma, prostate and bladder cancer. Previous research suggested that miR-875 is implicated in the development of cervical cancer cells. However, the exact role and function of miR-875-5p in cervical cancer remain unexplored. It is important to examine the role and function of miR-875-5p and the associated signaling pathway, as the findings may have diagnostic and therapeutic significance. Thus, in this study, we investigated the effect of miR-875-5p on the growth and metastasis of cervical cancer cells and the possible underlying mechanisms. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of miR-875-5p in cervical cancer cells and normal cervical epithelium. After overexpression or co-expression of miR-875-5p in cells, the changes in cell function were analyzed. Western blot was used to detect the expression changes of epithelial-mesenchymal transition (EMT) -related proteins and autophagy-related proteins. Functional studies demonstrated that miR-875-5p overexpression significantly inhibited the proliferation, migration, invasion, and EMT, and promotes apoptosis and autophagy of cervical cancer cells., while miR-875-5p knockdown promoted the proliferation, migration, invasion, and EMT, and inhibited apoptosis and autophagy cervical cancer cells. Furthermore, Western blot results showed that overexpression of miR-875-5p downregulated the expressions of N-cadherin, Snail, Vimentin and microtubule-associated protein 1 light chain 3B I (LC3B I). Conversely, miR-875-5p upregulated the expression of E-cadherin. In conclusion, our findings suggest that miR-875-5p functions as a tumor inhibitor suppressing the growth and metastasis of cervical cancer. Overexpression of miR-875-5p inhibits malignant behavior and promotes autophagy and apoptosis in cervical cancer cells. These findings advance our understanding of the role and function of miR-875-5p in cervical cancer and could facilitate the development of early genetic markers or biomarkers and therapeutic targets for cervical cancer.

Deoxyshikonin triggers apoptosis in cervical cancer cells through p38 MAPK-mediated caspase activation.

Deoxyshikonin (DSK) is a biological component derived from Lithospermum erythrorhizon. Although DSK possesses potential anticancer activities, whether DSK exerts anticancer effects on cervical cancer cells is incompletely explored. This study was aimed to investigate the anticancer activity of DSK against cervical cancer cells and its molecular mechanisms. Cell viability was evaluated by MTT assay. Level of phosphorylation and protein was determined using Western blot. Involvement of signaling kinases was assessed by specific inhibitors. Our results revealed that DSK reduced viability of human cervical cell in a dose-dependent fashion. Meanwhile, DSK significantly elicited apoptosis of HeLa and SiHa cells. Apoptosis microarray was used to elucidate the involved pathways, and the results showed that DSK dose-dependently diminished cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, and XIAP, and induced cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-8/9/3. Furthermore, we observed that DSK significantly triggered activation of ERK, JNK, and p38 MAPK (p38), and only inhibition of p38 diminished the DSK-mediated pro-caspases cleavage. Taken together, our results demonstrate that DSK has anti-cervical cancer effects via the apoptotic cascade elicited by downregulation of IAPs and p38-mediated caspase activation. This suggests that DSK could act as an adjuvant to facilitate cervical cancer management.

The Role of SARS-CoV-2 Spike Protein in the Growth of Cervical Cancer Cells.

Recently developed vaccines for the SARS-CoV-2 virus utilize endogenous production of the virus' spike protein (SP), allowing the host to develop an immune response. As a result of the novelty of this virus and its vaccines, little is known overall about the potential effects of the SP on the pathogenesis of neoplasia, either from vaccination or from infection. This study was designed to investigate whether SARS-CoV-2 SP has any direct effect on SiHa cervical cancer cells. The effects of SARS-CoV-2 SP on cervical cancer cell proliferation and apoptosis were investigated by using clonogenic cell survival assay, quick cell proliferation assay, and caspase-3 activity kits in a widely-used cervical cancer cell line, SiHa. RT-PCR and immunohistochemistry were also performed to determine the potential molecular mechanisms. The growth and proliferation of SiHa cancer cells were inhibited by SARS-CoV-2 SP. SARS-CoV-2 SP also induced apoptosis in SiHa cancer cells. The anti-proliferative effect of SARS-CoV-2 SP on SiHa cancer cells was associated with the up-regulation of the anti-proliferative molecule p53. The pro-apoptotic effect of SARS-CoV-2 SP on SiHa cells was associated with the up-regulation of the pro-apoptotic molecule TRAIL. SARS-CoV-2 SP inhibits the growth of cervical cancer via up-regulation of p53 and TRAIL. Further studies are needed to elaborate on the potential effects of the SARS-CoV-2 SP on other cancer cell lines and normal physiological cell lines for comparison.

Norcantharidin Enhances the Antitumor Effect of 5-Fluorouracil by Inducing Apoptosis of Cervical Cancer Cells: Network Pharmacology, Molecular Docking, and Experimental Validation.

The high recurrence rate of cervical cancer is a leading cause of cancer deaths in women. 5-Fluorouracil (5-FU) is an antitumor drug used to treat many types of cancer, but its diminishing effectiveness and side effects limit its use. Norcantharidin (NCTD), a demethylated derivative of cantharidin, exhibits various biological activities. Here, we investigated whether NCTD could potentiate 5-FU to induce cervical cancer cell death. To assess the cell viability and synergistic effects of the drugs, cell counting kit-8 and colony formation assays were performed using HR-HPV-positive cervical cancer cell lines. Annexin V-FITC/PI staining and TUNEL assays were performed to confirm the induction of apoptosis. The synergistic effect of NCTD on the antitumor activity of 5-FU was analyzed using network pharmacology, molecular docking, and molecular dynamics simulations. Apoptosis-related proteins were examined using immunoblotting. The combination of NCTD and 5-FU was synergistic in cervical cancer cell lines. Network pharmacological analysis identified 10 common targets of NCTD and 5-FU for cervical cancer treatment. Molecular docking showed the strong binding affinity of both compounds with CA12, CASP9, and PTGS1. Molecular dynamics simulations showed that the complex system of both drugs with caspase-9 could be in a stable state. NCTD enhanced 5-FU-mediated cytotoxicity by activating apoptosis-related proteins. NCTD acts synergistically with 5-FU to inhibit cervical cancer cell proliferation. NCTD enhances 5-FU-induced apoptosis in cervical cancer cell lines via the caspase-dependent pathway.