Drug Development Research

Andrographolide Mitigates Cisplatin Resistance by Inhibiting SPP1 Regulated NF‐kB/iNOS/COX‐2 and PI3K/AKT Pathway in Cisplatin Resistant Cervical Carcinoma Cells

ABSTRACTDrug resistance and cancer recurrence are major cause of Cervical cancer (CC) patient mortality. Cisplatin (CDDP) is the major drug that has been extremely used in all stages in treating CC, although relapse and malignant instances have been observed as a result of cisplatin resistance in CC. In the present study, we established Cisplatin resistant CC HeLa cell line model and the cytotoxic effects of Andro as a single agent or in combination with CDDP were investigated to assess its potential as a chemotherapeutic agent in cisplatin‐resistant HeLa (CisR‐HeLa) cells. Andro enhanced the cytotoxicity of CDDP in CisR‐HeLa cells and shown a synergistic effect by reducing cell viability, proliferation, migration, invasion, and inducing apoptosis in cisplatin resistant cells. Furthermore, we evaluated the expression levels of inflammatory and oncogenic proteins, SPP1, NF‐kB, iNOS, COX‐2, and the PI3K/AKT signaling pathway, which are associated with cisplatin resistance, as well as using Andro to regulate the targeted markers in CisR‐HeLa cells to overcome resistance. The results show that suppressing SPP1 and NF‐kB by Andro alone or in combination with CDDP regulates iNOS, COX‐2, and increases PTEN expression. The addition of Andro to CDDP inhibited PI3K and AKT expression as well as triggered synergistic apoptosis, which could be associated with variations in Bax and Bcl‐2 protein levels. The results suggest that Andro in combination with CDDP exhibits synergistic anti‐tumor growth efficacy that targets multiple inflammatory markers, resulting in a promising treatment option for individuals with recurrent cancer due to drug resistance and advanced CC.

Synthesis and cytotoxic evaluation of apioarabinofuranosyl pyrimidines

AbstractIn view of the potent anticancer activity of the d‐arabino‐configured cytosine nucleoside (ara‐C), apioarabinofuranosyl pyrimidine nucleosides were designed and synthesized from d‐ribose as starting material. The synthetic strategy signifies that tosylation followed by in situ cyclization, one‐pot controlled oxidative cleavage and acetylation by Pb(OAc)4, stereoselective nucleobase condensation, inversion of hydroxyl group and uracil group converted to cytosine as the key steps. Synthesized apioarabinofuranosyl pyrimidine nucleosides were tested using breast, colon, and ovarian cancer cell lines. However, only compound 19a, 19b, and 22b have a moderate growth‐suppressive effect against the luminal A breast cancer cell line MCF7.

Receptor interacting protein kinase 4 promotes cell proliferation, migration, and invasion in ovarian cancer via targeting protein kinase C delta

AbstractReceptor interacting protein kinase 4 (RIPK4) has been reported to function as an oncogenic role in several types of cancers. The aim of this study was to evaluate the role of RIPK4 in ovarian cancer (OC) cells and to elucidate the mechanism behind this effect. In this study, the GEPIA database was used to analyze the RIPK4 expressions in OC tissues and overall survival. qRT‐PCR and western blot assay were performed to detect the expressions of RIPK4 and protein kinase C delta (PRKCD) in OC cells. In addition, cell proliferation was assessed by CCK‐8 and colony formation assay while cell invasion and migration were evaluated by transwell, wound healing and western blot assay. The interaction of RIPK4 and PRKCD was analyzed by the STRING database and the bioGRID database, and verified with co‐immunoprecipitation. Herein, we describe that RIPK4 expression was upregulated in OC tissues and cells and was associated with poor overall survival. RIPK4 silencing repressed the proliferation, migration, and invasion of OC cells. Mechanistically, PRKCD was highly expressed in OC cells and was combined with RIPK4. PRKCD was highly positively associated with RIPK4 in OC and was regulated by RIPK4. Moreover, PRKCD overexpression reversed the inhibitory effects of RIPK4 silencing on OC cell proliferation, migration, and invasion. RIPK4 functions as an oncogene in OC cells via at least partially binding to PRKCD, which might represent a novel therapeutic strategy for improving survival for patients with OC.

Investigating function of long noncoding RNA of HOTAIRM1 in progression of SKOV3 ovarian cancer cells

AbstractOvarian cancer is one of the most heterogeneous malignancies in the field of gynecologic oncology. Deregulation of long noncoding RNAs (lncRNAs) is implicated in carcinogenesis. Therefore, the present study was conducted to investigate the possible role of lncRNA of HOXA transcript antisense intergenic RNA myeloid‐specific 1(HOTAIRM1) in progression of SKOV3 cells in ovarian cancer and also its underlying molecular mechanisms. HOTAIRM1 expression level will be measured by real‐time polymerase chain reaction (PCR) in SKOV3 cells. For determining the effect of HOTAIRM1 silencing on progression of SKOV3 cells, siHOTAIRM1 will be designed and transfected into cells using a liposomal approach. MTT and trypan blue assays will be used to determine the effect of HOTAIRM1 silencing on cell proliferation. Apoptosis of the cells will be detected by flow cytometry. Furthermore, expressions of apoptosis‐related genes and Wnt pathway‐related proteins and genes will be analyzed by Western blot and real‐time PCR. HOTAIRM1 was overexpressed in SKOV3 cells. Silencing of HOTAIRM1 alleviated cell proliferation, and increased cell apoptosis of SKOV3 cells. Moreover, siHOTAIRM1 significantly increased expression of pro‐apoptotic agents, such as Bad and Bax, while it decreased expressions of Bid and Bcl‐2 (anti‐apoptotic agents). Also, silencing of HOTAIRM1 resulted in a suppressed expression of Wnt pathway‐related proteins and also expression of its downstream target gene, matrix metalloproteinase 9(MMP9). Our findings provided new insights into function of lncRNA of HOTAIRM1 in progression of ovarian cancer by modulating Wnt pathway and its downstream target gene, MMP9.

Icariside II suppresses the tumorigenesis and development of ovarian cancer by regulating miR‐144‐3p/IGF2R axis

AbstractOvarian cancer is one of the three major gynecological malignancies. It has been reported that Icariside II was able to block the occurrence and development of ovarian cancer. However, the detailed mechanism by which Icariside II regulates the development of ovarian cancer is widely unknown. EdU staining and transwell assays were applied to detect the proliferation, migration, and invasion of ovarian cancer cells. Next, the relationship between miR‐144‐3p and IGF2R was verified by the dual‐luciferase reporter assay. Moreover, in vivo animal model was constructed to verify the effect of Icariside II on the development of ovarian cancer. Icariside II notably inhibited the proliferation, migration, and invasion and induced the apoptosis of ovarian cancer cells. Additionally, Icariside II markedly increased the level of miR‐144‐3p in ovarian cancer cells. Moreover, IGF2R was targeted by miR‐144‐3p directly. Icariside II significantly decreased the expression of IGF2R and the phosphorylation level of AKT and mTOR in ovarian cancer cells, which were partially reversed by miR‐144‐3p inhibitor. Meanwhile, Icariside II remarkably promoted the autophagy of ovarian cancer cells, as confirmed by the increased expression of Beclin‐1 and ATG‐5 and decreased expression of p62; however, co‐treatment with miR‐144‐3p inhibitor notably decreased autophagy. Furthermore, the result of animal study suggested Icariside II notably inhibited ovarian tumor growth as well. Collectively, Icariside II could suppress the tumorigenesis and development of ovarian cancer by promoting autophagy via miR‐144‐3p/IGF2R axis. These results may be beneficial for future studies on the use of Icariside II to treat ovarian cancer.

CircMYBL2 regulates the resistance of cervical cancer cells to paclitaxel via miR‐665‐dependent regulation of EGFR

AbstractCircular RNAs are considered to be associated with cancer resistance. This study aims to investigate the function and mechanism of circMYBL2 in paclitaxel (PTX) resistance of cervical cancer (CC). The expression of circMYBL2, miR‐665 and epidermal growth factor receptor (EGFR) was investigated using quantitative real‐time polymerase chain reaction assay. Cell viability, cell colony number, cell proliferation, apoptosis and lactate dehydrogenase (LDH) were detected by 3‐(4, 5‐Dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide, colony formation, 5‐ethynyl‐2′‐deoxyuridine incorporation, flow cytometry and LDH release assays, respectively. The interaction between miR‐665 and circMYBL2 or EGFR was confirmed by dual‐luciferase reporter assay. The protein expression levels were quantified by western blot or immunohistochemistry assay. Mice xenograft models were constructed to investigate the effect of circMYBL2 on CC tumor growth. CircMYBL2 was upregulated in CC tissues and cells, especially in PTX‐resistant CC tissues and cells, and it was a stable circRNA mainly distributed in the cytoplasm. CircMYBL2 could enhance the PTX resistance of CC cells in vitro and promote CC tumor growth in vivo. Mechanistically, circMYBL2 could inhibit the PTX sensitivity and promote cell malignant behaviors in PTX‐sensitive and PTX‐resistant CC cells via upregulating EGFR mediated by miR‐665. CircMYBL2 played a positive role in the PTX resistance and malignant activities of PTX‐sensitive and PTX‐resistant CC cells by regulating the miR‐665/EGFR network, providing a novel therapeutic strategy for the treatment of CC patients resistant to PTX.

CircFAT1 facilitates cervical cancer malignant progression by regulating ERK1/2 and p38 MAPK pathway through miR‐409‐3p/CDK8 axis

AbstractCircular RNA FAT atypical cadherin 1 (circFAT1) has been reported to play vital roles in the progression of some cancers. However, the regulatory role and underlying mechanisms of circFAT1 in cervical cancer (CC) remain largely unknown. The expression of circFAT1, microRNA (miR)‐409‐3p and cyclin‐dependent kinase 8 (CDK8) was detected using qRT‐PCR and Western blot assays. Cell proliferation, apoptosis, migration and invasion in vitro were investigated using cell counting kit‐8, colony formation, flow cytometry, and transwell assays, respectively. Western blot assay was used to determine the activation of ERK1/2 and p38 MAPK pathway. The interaction miR‐409‐3p and circFAT1 or CDK8 was confirmed by dual‐luciferase reporter, pull‐down or RIP assays. The effects of circFAT1 in vivo were determined using xenograft models. CircFAT1 was highly expressed in CC, and closely associated with poor prognosis. CircFAT1 knockdown resulted in the suppression of proliferation, migration and invasion, and promotion of apoptosis in CC cells via the inactivation of ERK1/2 and p38 MAPK pathway; also, circFAT1 silencing could inactivate this pathway and repressed CC tumor growth in vivo. Mechanistic analysis showed that circFAT1 directly sponged miR‐409‐3p and then relieved the repressive effect of miR‐409‐3p on its target CDK8. Furthermore, miR‐409‐3p inhibition reversed the effects of circFAT1 silencing on CC cells. Whereas, miR‐409‐3p overexpression impeded CC cell growth and motility, which was attenuated by CDK8. CircFAT1 promoted CC progression via activating ERK1/2 and p38 MAPK pathway through the miR‐409‐3p/CDK8 axis, suggesting a promising prognostic biomarker and therapeutic target for CC.

9‐Ethynyl noscapine induces G2 /M arrest and apoptosis by disrupting tubulin polymerization in cervical cancer

Noscapine is a phthalide isoquinoline alkaloid present in the latex of Papaver somniferum and has demonstrated potent antitumor activity in various cancer models. Structural changes in the core molecule of noscapine architecture have produced a number of potent analogs. We have recently synthesized the novel noscapine analogs (3, 4, and 5) with different functional groups appended at ninth position of natural noscapine. The anticancer activity of these compounds has been investigated using various human cancer cell lines such as HeLa (cervical cancer), DU-145 (prostate cancer), MCF-7 (breast cancer), and IMR-32 (neuroblastoma). One of the compounds in this series, 9-ethynyl noscapine (5), has demonstrated good anticancer activity against HeLa cells. Biological studies demonstrated that compound 5 decreased cell viability and colony formation in HeLa cells in a concentration dependent manner. To further uncover the mechanism in detail, we evaluated compound 5 effect on cell cycle progression, microtubule dynamics, and apoptosis. Cell cycle and western blotting analysis revealed that 9-ethynyl noscapine treatment resulted in cell cycle arrest at G2/M and decreased CDK1 and cyclinB1 protein expression. We also observed that 9-ethynyl noscapine (5) treatment leads to disruption in tubulin polymerization and induction of apoptosis by decreasing expression of bcl2, pro-caspase 3, and activation of cytochrome C. Taken together, our results indicate that 9-ethynyl noscapine (5) effectively supresses the growth of cervical cancer cells (HeLa) by disrupting tubulin polymerization, cell cycle progression leading to apoptosis.

Overexpression of ARHI increases the sensitivity of cervical cancer cells to paclitaxel through inducing apoptosis and autophagy

AbstractCervical cancer (CC) is a common malignant tumor of the female reproductive system. This study investigated the role of aplysia ras homolog I (ARHI) in resistance to CC in vitro and in patients' tissues. Hela cells were continuously treated with different concentrations of paclitaxel (1–10 nM) to construct paclitaxel‐resistant cell model (Hela‐TR). CC or CC‐TR tissues were obtained from CC patients or CC patients who had developed paclitaxel resistance. The level of ARHI and multidrug resistance gene 1 (MDR1) in cells and tissues were detected by qRT‐PCR and immunohistochemistry (IHC) staining. Cell viability, apoptosis and the number of colonies were assessed by MTT, flow cytometry and cell clone assay in Hela and Hela‐TR cells after the ARHI plasmid or shARHI were transfected into cells. The autophagy and apoptosis signaling related proteins were analyzed by western blotting. The results revealed that the levels of ARHI mRNA and protein were down‐regulated in CC tissues, and were further reduced in paclitaxel‐resistant tissues and Hela cell model. High expression of ARHI inhibited the expression of MDR1 in Hela and Hela‐TR cells. The cell viability and cell clone of Hela and Hela‐TR cells were decreased by ARHI overexpression but increased by ARHI suppression. In addition, highly expressed ARHI promoted apoptosis and activated autophagy by increasing LC3‐II/LC3‐I through inactivating AKT/mTOR signaling pathway. In conclusion, overexpression of ARHI can increase the sensitivity of CC to paclitaxel through promoting apoptosis and autophagy in a AKT/mTOR inactivation dependent pathway.

Ricolinostat suppresses proliferation, promotes apoptosis, and enhances the antiproliferative activity of topoisomerase inhibitors in cervical cancer cells

AbstractRicolinostat has been found to exhibit anticancer effects alone and in combination with various chemotherapeutic drugs in several cancer types. However, to the best of our knowledge, the efficacy of ricolinostat in cervical cancer is still not investigated. Therefore, in this study, we evaluated the effect of ricolinostat in cervical cancer alone and in combination with topoisomerase inhibitors. The effect of ricolinostat on cervical cancer cells was assessed using MTT, cell‐cycle arrest, Annexin V/PI staining assay, reactive oxygen species (ROS) measurement, and western blot analysis. The antiproliferative effect of ricolinostat in combination with topoisomerase inhibitors was assessed using the MTT assay and synergism was computed using “CompuSyn” software. We found that ricolinostat inhibited proliferation, and induced G2/M phase arrest and apoptosis in cervical cancer cells. We further found that ricolinostat treatment resulted in increased ROS production, decreased Bcl‐xL expression, and induced p21 expression. We also investigated the effect of ricolinostat in combination with topotecan and etoposide in cervical cancer cells. Ricolinostat was found to significantly enhance the antiproliferative activity of both, topotecan and etoposide, in cervical cancer cells in a concentration‐dependent manner. In conclusion, our study showed that ricolinostat suppressed proliferation by inducing G2/M phase arrest and promoted apoptosis in cervical cancer cells, indicating that ricolinostat may be a promising antitumor agent in cervical cancer. Also, ricolinostat and topotecan/etoposide combination are synergistic in cervical cancer cells.

α‐Pinene inhibits the growth of cervical cancer cells through its proapoptotic activity by regulating the miR‐34a‐5p/Bcl‐2 signaling axis

Abstract Among gynecological tumors, cervical cancer (CC) has the second‐highest prevalence and mortality rate. α‐Pinene is a bicyclic monoterpenoid compound extracted from pine needles that carried promising anticancer properties. Nevertheless, its effect on CC and the underlying mechanism has not yet been elucidated. Therefore, we investigated the effect of α‐Pinene on apoptosis in CC via in vitro assays of flow cytometry (FCW), terminal deoxynucleotidyl transferase‐mediated nick end labeling (TUNEL) assay, quantitative real‐time polymerase chain reaction (qRT‐PCR), and Western blot. Following that, we detected the proapoptotic function of α‐Pinene on HeLa cells in vivo by TUNEL assay and immunofluorescence staining. Our results displayed that the α‐Pinene inhibited the growth of HeLa cells and stalled the cells in the G0/G1 phase. Interestingly, we also detected that α‐Pinene induced HeLa cells to apoptosis. The results investigated that α‐Pinene induced HeLa cells apoptosis along with up‐regulating the expression of Bax, Bid, caspase‐9, caspase‐3, miR‐34a‐5p, and down‐regulating the expression of Bcl‐2 in vitro. At the same time, the expression levels of target genes in vivo were consistent with those in vitro. Our experiment proved that α‐Pinene promoted apoptosis, which will be used to hopefully maximize the therapeutic strategies in clinical studies in CC.

YTHDF2 interference suppresses the EMT of cervical cancer cells and enhances cisplatin chemosensitivity by regulating AXIN1

AbstractM6A reader YTH structural domain family 2 (YTHDF2) has been recognized to play an oncogenic role in numerous tumors, but its role in cervical cancer has not been extensively discussed yet. This paper was designed to explore the role of YTHDF2 in cervical cancer and identify its underlying mechanism. The expression of YTHDF2 was first determined in cervical cancer cells by quantitative reverse‐transcription polymerase chain reaction and western blot. Then, the migration, invasion, and epithelial–mesenchymal transition (EMT) process were observed in YTHDF2‐knockdown Hela cells using wound healing, transwell and immunofluorescence assays. The cisplatin chemosensitivity of Hela cells was also investigated by assessing cell activity with cell counting kit‐8 and TUNEL (terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling). After MeRIP‐Seq assay and actinomycin D treatment to confirm the binding relationship between YTHDF2 and AXIN1, the migration, invasion, EMT process, and cisplatin chemosensitivity were assessed again in Hela cells silenced by YTHDF2 and AXIN1 or treated with Wnt agonist. YTHDF2 was increased in cervical cancer cells, and depletion of YTHDF2 led to reduced migration, invasion and EMT process but enhanced chemosensitivity of cisplatin in Hela cells. Furthermore, YTHDF2 could bind to and stabilize the expression of AXIN1. When the YTHDF2‐knockdown Hela cells were further transfected with AXIN1 knockdown or treated with Wnt agonist, the effects of YTHDF2 knockdown on the migration, invasion and EMT process were partially abolished, together with reduced cisplatin chemosensitivity. To sum up, we reported that YTHDF2 interference could suppress the EMT of cervical cancer cells and enhance cisplatin chemosensitivity by regulating AXIN1.

CircRNF121 knockdown suppresses the progression of cervical cancer by regulating miR ‐153‐3p/ ATF2 axis and wnt/β‐catenin pathway

Cervical cancer (CC) is a common malignancy in gynecology. Emerging evidence has demonstrated that circular RNAs (circRNAs) act as vital mediators in CC. However, the roles of circRNA ring finger protein 121 (circRNF121) in CC are largely unknown. Herein, we focused on the exact function and underlying mechanism of circRNF121 in CC development. Our results showed that circRNF121 was highly expressed in CC tissues and cells. Knockdown of circRNF121 suppressed cell growth, metastasis, epithelial-mesenchymal transition (EMT), autophagy, and wnt/β-catenin pathway in CC cells in vitro and blocked tumor formation in vivo. For mechanism investigation, circRNF121 could affect activating transcription factor 2 (ATF2) expression by decoying miR-153-3p, thereby accelerating CC cell development. In conclusion, circRNF121 exerted the tumor-suppressive role in CC progression by altering miR-153-3p/ATF2 axis. These results suggested that circRNF121 might be a possible circ-targeted therapy for patients with CC.

Antiproliferative Effects of the Triterpene Ursolic Acid Natural Product in Bladder and Ovarian Tumor Cell Lines

ABSTRACT Bladder and ovarian cancers impose a significant burden on healthcare systems due to their high incidence, mortality rates, and the challenges associated with early diagnosis. Current chemotherapy regimens, which typically involve combinations of drugs, often cause severe side effects that negatively impact patient adherence and treatment efficacy. Recently, studies have explored the use of herbal medicines to mitigate the adverse effects of chemotherapy. One such herbal compound is ursolic acid (UA), a triterpene known for its anti‐inflammatory, antioxidant, and antitumor properties. This study aimed to evaluate the effects of UA on bladder and ovarian cancer cells harboring TP53 mutations through various assays, including cytotoxicity, clonogenic survival, cell migration, morphological changes, apoptosis, cell cycle analysis, JHDM1D expression and selectivity using MRC‐5 cells, along with in silico evaluation. The treatment demonstrated selectivity for tumoral cells and significant antiproliferative effects in both cell types, leading to decreased cell viability, reduced colony‐forming ability, inhibited cell migration, morphological changes characteristic of cell death, and increased expression of JHDM1D . In conclusion, UA exhibited antiproliferative activity against bladder and ovarian cancer cell lines with different TP53 mutation sites, suggesting its potential as a promising therapeutic alternative. Moreover, our study demonstrated for the first time the presence of UA in the species F. formosa .

Disruption of the FOXM1 Regulatory Region Inhibits Tumor Progression in Ovarian Cancer by CRISPR‐Cas9

ABSTRACTOvarian cancer is the seventh most common lethal tumor among women in the world. FOXM1 is a transcription factor implicated in the initiation and progression of ovarian cancer by regulating key oncogenic genes. The role of regulatory regions in regulating the expression of FOXM1 in ovarian cancer is not completely clarified. Treatment with bromodomain and extraterminal (BET) inhibitors JQ‐1 and I‐BET were explored in ovarian cancer cell lines (OVCAR3, A2780, or SKOV3) to evaluate FOXM1 expression and biological behavior by qPCR, CCK8 assay, colony formation assay, wound‐healing, and transwell assays. The regulatory regions (enhancer sequence spanning promoter or exon 1) of FOXM1 were deleted using CRISPR‐Cas9 in the OVCAR3 cell line. FOXM1 expression and tumor biological behavior were further assessed in FOXM1 regulatory regions deleted OVCAR3 cell line. The mouse xenograft model was assessed at the indicated time points following subcutaneous injection of enhancer‐deleted cells. Treatment with the JQ‐1 and I‐BET reduced the expression of FOXM1, decreasing cell proliferation, migration, and invasion in a panel of ovarian cancer cell lines including OVCAR3, A2780, and SKOV3 cells. By mining the published ChIP‐sequencing data (H3K27Ac) from 12 ovarian cancer cell lines, we identified a potential enhancer and promoter region. Deletion of the spanning enhancer and promoter region of FOXM1 reduced mRNA and protein expression. Similarly, cell proliferation, migration, invasion, and tumorigenesis in both cells and mouse xenograft models were significantly attenuated. Our study demonstrates that JQ‐1 and I‐BET can regulate the expression of the FOXM1 gene‐relating network. These data also indicate that disruption of the span enhancer and promoter region activity of FOXM1 has a vital role in the anti‐ovarian cancer effect, hiding a potential opportunity for the evaluation of this non‐coding DNA deletion disrupts the FOXM1 transcriptional network in ovarian cancer development.

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

AbstractCervical 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.

CircATL2 enhances paclitaxel resistance of ovarian cancer via impacting miR‐506‐3p/NFIB axis

AbstractCircular RNAs (circRNAs) play vital regulatory roles in the development of ovarian cancer (OC). However, the functions of circRNA Atlastin GTPase 2 (circATL2) in paclitaxel (PTX) resistance of OC are still unclear. As a result, circATL2 was upregulated in PTX‐resistant OC tissues and cells. CircATL2 knockdown reduced IC50 of PTX, inhibited colony formation ability and promoted cell cycle arrest and apoptosis in PTX‐resistant OC cells. Silencing of circATL2 restrained PTX resistance in vivo. Furthermore, miR‐506‐3p could be targeted by circATL2 and miR‐506‐3p inhibition reversed the impacts of circATL2 knockdown on PTX resistance and cell progression in PTX‐resistant OC cells. NFIB was identified as the target of miR‐506‐3p. MiR‐506‐3p overexpression suppressed PTX resistance and malignant behaviors of PTX‐resistant OC cells, with NFIB elevation rescued the impacts. To summarize, circATL2 promoted the resistance of OC to PTX by sponging miR‐506‐3p to upregulate NFIB expression, providing a new sight in chemoresistance of OC.