Chemosensitivity Of Ovarian Cancer Cells Research Articles

Anlotinib Inhibits Ovarian Cancer and Enhances Cisplatinum Sensitivity via Suppressing NOTCH2 Expression and Stemness.

The prognosis of ovarian cancer (OC) patients is especially poor for patients with chemotherapy resistance. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor, has shown encouraging clinical efficacy in several tumor types. The aim of the present study was to examine the inhibitory efficacy and mechanism of anlotinib on the proliferation and chemosensitivity of OC cells. The inhibitory effects of Anlotinib on SKOV3 and OVCAR3 OC cells were examined using CCK-8 cell-viability, colony-formation, flow-cytometry, transwell-migration and sphere-formation assays. A xenograft mouse model was used for in vivo studies. RT-qPCR and western blotting were used to detect gene expression. Molecular targets of anlotinib were elevated in OC patient tumors. Anlotinib significantly inhibited ovarian cancer cell proliferation and migration in vitro. Anlotinib enhanced the sensitivity of ovarian cancer cells to cisplatinum both in vitro and in vivo. Anlotinib suppressed sphere formation and the stemness phenotype of OC cells by inhibiting NOTCH2 expression. Anlotinib inhibits ovarian cancer and enhances cisplatinum sensitivity, suggesting its future clinical promise.

CUL3/SPOP complex prevents immune escape and enhances chemotherapy sensitivity of ovarian cancer cells through degradation of PD-L1 protein

BackgroundCancer immune escape is a main obstacle in designing effective anticancer therapeutic approaches. Our work was aimed to explore the function of cullin 3 (CUL3) in ovarian cancer cell immune...

310 (PB090) - Metabolic profile associated with chemoresistance in ovarian cancer cells using metabolomics

Background: Ovarian cancer (OvCa) is the fifth leading cause of cancer death in women worldwide and the second leading cause of death of all gynecological malignancies. Although the incidence is not that high, mortality is about 70%, due mainly to its high recurrence rate, despite chemotherapy and targeted therapy. Factors such as invasiveness, metastatic properties, and response to treatment affect disease prognosis and survival. This work uses a metabolomics approach to identify metabolites from chemoresistant and chemosensitive ovarian cancer cells.

Abstract 1551: miR-625-3p enhances chemosensitivity in ovarian cancer cells through exosomal export of cisplatin and paclitaxel

Abstract Although a majority of women with high-grade serous ovarian cancer (HGSC) achieve a complete response to first-line platinum- and paclitaxel-based chemotherapy, around thirty percent of patients are identified as incomplete responders. Their diseases typically either does not respond or progresses during treatment (refractory) or recurs within 6 months of completing treatment (resistant), suggesting the inherit or intrinsic characteristics of the tumor. Currently, there are no biomarkers that can predict intrinsic resistance, which can avoid unnecessary treatment and toxicity. MicroRNAs (miRNAs) provide a novel master layer of regulation of gene expression. However, the molecular mechanisms by which miRNAs confer a chemoresistant phenotype in ovarian cancer have not been elucidated. To identify miRNAs that are associated with intrinsic chemoresistance in HGSC, Ion Torrent next-generation sequencing analysis of miRNAs was performed on microdissected chemosensitive and chemorefractory primary HGSC cases. Amongst all the miRNAs that were significantly down-regulated in chemorefractory cases, lower miR-625-3p expression was found to be associated with poorer overall and progression-free survivals. Further functional studies showed that overexpression of miR-625-3p significantly decreased cisplatin and paclitaxel resistance in ovarian cancer cells in vitro and in vivo. Online target prediction algorithms together with transcriptome profiling of HGSC cells transfected with miR-625-3p mimics or control mimics identified SSX2IP as a direct target of miR-625-3p, suggesting that SSX2IP may play a role in conferring cisplatin/paclitaxel resistance in HGSC by mediating the effect of miR-625-3p. SSX2IP is a microtubule anchoring and centriolar satellite protein, which plays a critical role in controlling microtubule length and orientation, and centrosome maturation. We demonstrated that HGSC cells transfected with SSX2IP had marked increases in microtubule masses, intracellular multivesicular body trafficking and exosomal cisplatin level; and a decrease in intracellular cisplatin level. In conclusion, down-regulation of miR-625-3p confers cisplatin/paclitaxel resistance in ovarian cancer cells via its novel direct target SSX2IP. SSX2IP alters the microtubule dynamics and subsequently mediates inter-organelle crosstalks between microtubules and multivesicular bodies, which facilitate exosomal export of cisplatin and paclitaxel of HGSC cells. This study is crucial for developing new predictive biomarkers for intrinsic chemoresistance, and new treatment strategies for HGSC based on upregulating miR-625-3p or downregulating SSX2IP expression in ovarian cancer cells, which will enhance cisplatin and paclitaxel sensitivity, and improve patient survival rates. Citation Format: Chi Lam Au Yeung, Tetsushi Tsuruga, Kay-Pong Yip, Sammy Ferri-Borgogno, Samuel Mok. miR-625-3p enhances chemosensitivity in ovarian cancer cells through exosomal export of cisplatin and paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1551.

Abstract 965: 5-Aza-dC treatment impacts the microtubule network to decrease metastatic potential through reduced cell clustering and attachment

Abstract Melanoma cell adhesion molecule (MCAM) is a protein located on the cell surface that was first discovered in advanced primary tumors and metastatic lesions. Overexpression of MCAM is associated with triple-negative breast cancer, decreased patient survival, and induces vimentin and slug indicative of an epithelial to mesenchymal transition (EMT). Additionally, breast cancer cell lines overexpressing MCAM show an increase in migration, invasion, and tumorigenesis. Given that overexpressed MCAM causes increased migration and invasion in multiple cancer types, MCAM could be one of the major contributors to recent studies showing increased metastatic phenotypes with certain cancer treatments. Decitabine (5-Aza-dC) is a chemotherapeutic used for acute myeloid leukemias with clinical trials underway for breast cancer use. 5-Aza-dC results in the depletion of DNA methyltransferase and acts as a demethylating agent. In 2019, 5-Aza-dC was reported to increase mRNA and protein levels of MCAM in various breast cancer cell lines, followed by an increase in EMT markers. Studies suggest that 5-Aza-dC treatment in chemo-sensitive ovarian cancer cell lines results in increased EMT markers as well as increased invasion and migration. Microtubules are a very common target of multiple cancer therapies. However, the impact of 5-Aza-dC and MCAM on the microtubule network and non-adherent cells has not been well studied. We set out to explore changes in microtentacle (McTN), cell attachment and clustering, and microtubule modifications due to 5-Aza-dC treatment and MCAM expression. Treatment of MCF10A, MCF10A variants, and MCF7 breast cancer cell lines with 5-Aza-dC showed consistent increases in the expression of MCAM. When exploring the effects of 5-Aza-dC treatment on the cytoskeleton, specifically microtubules, it was found that there is a significant increase in acetyl tubulin and detyrosinated tubulin, two common microtubule modifications correlated with an increase of McTNs. However, there was not a significant increase in the number of cells with McTNs in treated cells. Since McTNs can aid in attachment and cell clustering, attachment assays and clustering assays were performed after 5-Aza-dC treatment. These experiments showed that 5-Aza-dC decreased the ability of all cell lines to attach and impeded these cells' ability to form clusters. While there are emerging concerns that Decitabine can increase metastatic phenotypes of migration and invasion in adherent cells, our results indicate that within a non-adherent environment, Decitabine reduces the metastatic phenotypes of clustering and reattachment. Ongoing experiments focus on testing the impact of stable genetic alterations in these cell lines to examine the specific impact of MCAM overexpression on the microtubule network and metastatic potential. Citation Format: David Annis, Keyata Thompson, Julia Ju, Makenzy Mull, Trevor Mathias, Michele Vitolo, Stuart Martin. 5-Aza-dC treatment impacts the microtubule network to decrease metastatic potential through reduced cell clustering and attachment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 965.

Effects of trans-(±)-kusunokinin on chemosensitive and chemoresistant ovarian cancer cells.

Ovarian cancer ranks eighth in cancer incidence and mortality among women worldwide. Cisplatin-based chemotherapy is commonly used for patients with ovarian cancer. However, the clinical efficacy of cisplatin is limited due to the occurrence of adverse side effects and development of cancer chemoresistance during treatment. Trans-(±)-kusunokinin has been previously reported to inhibit cell proliferation and induce cell apoptosis in various cancer cell types, including breast, colon and cholangiocarcinoma. However, the potential effects of (±)-kusunokinin on ovarian cancer remains unknown. In the present study, chemosensitive ovarian cancer cell line A2780 and chemoresistant ovarian cancer cell lines A2780cis, SKOV-3 and OVCAR-3 were treated with trans-(±)-kusunokinin to investigate its potential effects. MTT, colony formation, apoptosis and multi-caspase assays were used to determine cytotoxicity, the ability of single cells to form colonies, induction of apoptosis and multi-caspase activity, respectively. Moreover, western blot analysis was performed to determine the proteins level of topoisomerase II, cyclin D1, CDK1, Bax and p53-upregulated modulator of apoptosis (PUMA). The results demonstrated that trans-(±)-kusunokinin exhibited the strongest cytotoxicity against A2780cis cells with an IC50 value of 3.4 µM whilst also reducing the colony formation of A2780 and A2780cis cells. Trans-(±)-kusunokinin also induced the cells to undergo apoptosis and increased multi-caspase activity in A2780 and A2780cis cells. This compound significantly downregulated topoisomerase II, cyclin D1 and CDK1 expression, but upregulated Bax and PUMA expression in both A2780 and A2780cis cells. In conclusion, trans-(±)-kusunokinin suppressed ovarian cancer cells through the inhibition of colony formation, cell proliferation and the induction of apoptosis. This pure compound could be a potential targeted therapy for ovarian cancer treatment in the future. However, studies in an animal model and clinical trial need to be performed to support the efficacy and safety of this new treatment.

Isothiocyanate Iberin inhibits cell proliferation and induces cell apoptosis in the progression of ovarian cancer by mediating ROS accumulation and GPX1 expression

Ovarian cancer (OC) is one of the most common gynecologic malignancies with poor survival rate, and Iberin is a member of isothiocyanate family with anti-tumor activity. However, the role of Iberin in OC development has not been reported yet. In this study, A2780 and OVCAR-3 cells were treated with gradient concentrations of Iberin to investigate the effect of Iberin on OC in vitro. Meanwhile, the in vivo tumorgenesis experiment was performed using female BALB/c nude mice treated with Iberin. Iberin inhibited cell proliferation, induced G2 cell cycle arrest and promoted cell apoptosis in OC cells. Besides, Iberin reduced GSH/GSSG level, enhanced ROS accumulation, and activated MAPK signaling in OC cells. More interestingly, ROS scavenger (NAC) compensated the anti-proliferative and pro-apoptotic effects of Iberin on OC cells, suggesting the involvement of ROS in the regulation of Iberin on OC cell growth. Notably, Iberin induced down-regulation of glutathione peroxidase-1 (GPX1), and over-expression of GPX1 reversed Iberin-mediated alterations in the proliferation, apoptosis and ROS accumulation of OC cells. The in vivo tumorgenesis study further evidenced the protection of Iberin against OC development. Besides, Iberin displayed a synergistic effect on the enhancement of chemo-sensitivity in OC cells. In summary, our study demonstrates the anti-tumor effect of Iberin on OC and its potential as a therapeutic agent against OC in the future.

Knockout of vasohibin-2 reduces tubulin carboxypeptidase activity and increases paclitaxel sensitivity in ovarian cancer.

Vasohibin‐1 (VASH1) is a VEGF‐inducible endothelium‐derived angiogenesis inhibitor, and vasohibin‐2 (VASH2), its homolog, exhibits proangiogenic activity. VASH2 is expressed by various cancer cells and accelerates tumor angiogenesis and progression. VASH2 was recently shown to exhibit tubulin carboxypeptidase (TCP) activity related to microtubule functions. Paclitaxel (PTX), an effective chemotherapeutic agent that is widely used to treat ovarian cancer, inhibits microtubule depolymerization and may interact with VASH2. We herein established several VASH2 knockout ovarian cancer cell lines using the CRISPR/Cas9 genome editing system to examine the intracellular tubulin detyrosination status and PTX chemosensitivity. The knockout of VASH2 did not affect the proliferation or sphere‐forming activity of ovarian cancer cells in vitro. A Western blot analysis of VASH2 knockout cells revealed the weak expression of detyrosinated tubulin and upregulated expression of cyclin B1. The knockout of VASH2 significantly increased chemosensitivity to PTX, but not to cisplatin in ovarian cancer cell lines. The knockout of VASH2 reduced TCP activity and increased cyclin B1 expression, resulting in increased PTX chemosensitivity in ovarian cancer cells. The inhibition of angiogenesis and regulation of microtubule activity may be achieved in ovarian cancer treatment strategies targeting VASH2.

CREBBP knockdown suppressed proliferation and promoted chemo-sensitivity via PERK-mediated unfolded protein response in ovarian cancer.

CREBBP, in short CBP, has been reported to be involved in tumorigenesis in various cancers, but its role in ovarian cancer remains largely unexplored. In our study, survival analysis of CBP in patients with ovarian cancer was conducted using the Kaplan-Meier Plotter database, then we utilized specific shRNA targeting CREBBP to block the expression of CBP, and detected its effect on cell proliferation and chemo-sensitivity in ovarian cancer cells. The results showed that high expression of CBP was correlated with poor prognosis in ovarian cancer patients. CREBBP knockdown in ovarian cancer cells significantly inhibited tumor proliferation both in vitro and in vivo. Moreover, CREBBP knockdown promoted chemo-sensitivity in ovarian cancer cells. Mechanism research further demonstrated that CREBBP knockdown attenuated unfolded protein response (UPR), which was mediated by PERK/ATF4/STC2 signaling pathway. Our research linked CBP and UPR in ovarian cancer and may provide new strategies for the clinical treatment of ovarian cancer.

ABCA1 is associated with the development of acquired chemotherapy resistance and predicts poor ovarian cancer outcome.

Aim: This study investigated the ATP binding cassette (ABC) transporter (ABCA1, ABCB1, ABCB3, ABCC2 and ABCG2) expression in high grade serous ovarian cancer (HGSOC) tissues, cell lines and primary cells to determine their potential relationship with acquired chemotherapy resistance and patient outcome.Methods: ABC transporter mRNA and protein expression (ABCA1, ABCB1, ABCB3, ABCC2 and ABCG2) was assessed in publicly available datasets and in a tissue microarray (TMA) cohort of HGSOC at diagnosis, respectively. ABC transporter mRNA expression was also assessed in chemosensitive ovarian cancer cell lines (OVCAR-5 and CaOV3) versus matching cell lines with acquired carboplatin resistance and in primary HGSOC cells from patients with chemosensitive disease at diagnosis (n = 10) as well as patients with acquired chemotherapy resistance at relapse (n = 6). The effects of the ABCA1 inhibitor apabetalone in carboplatin-sensitive and -resistant cell lines were also investigated.Results: High ABCA1 mRNA and protein expression was found to be significantly associated with poor patient outcome. ABCA1 mRNA and protein levels were significantly increased in ovarian cancer cell lines (OVCAR-5 CBPR and CaOV3 CBPR) with acquired carboplatin resistance. ABCA1 mRNA was significantly increased in primary HGSOC cells obtained from patients with acquired chemotherapy resistance. Apabetalone treatment reduced ABCA1 protein expression and increased the sensitivity of both parental and carboplatin-resistant ovarian cancer cells to carboplatin.Conclusion: These results suggest that inhibiting ABCA1 transporter may be useful in overcoming acquired chemotherapy resistance and improving outcome for patients with HGSOC.

IL-17A/lL-17RA reduces cisplatin sensitivity of ovarian cancer SKOV3 cells by regulating autophagy

To investigate the effect of interleukin-17A (IL-17A) on chemosensitivity of ovarian cancer cells to cisplatin (DDP) and explore the mechanism in light of autophagy regulation. Ovarian cancer SKOV3 cells cultured in vitro were treated with different concentrations of DDP (1-20 μg/mL). MTT assay was used to observe the changes in proliferation of the treated cells and the effect of treatment with 100 ng/mL IL-17A for 24 h on DDP-induced apoptosis of SKOV3 cells. We then examined the expression of IL-17A receptor (IL-17RA) in SKOV3 cells using flow cytometry. Annexin V-FITC/PI double staining was used to detect the cell apoptosis rate, and early apoptosis of the cells was detected with JC-1 assay. A neutralizing monoclonal antibody (mAb) against IL-17RA was used to block IL-17RA. We also observed the effects of IL-17RA silencing mediated by a siRNA targeting IL-17RA (siRNA-IL-17RA) and treatment with 3-methyladenine (3-MA) for inhibiting autophagy on DDP-induced apoptosis of SKOV3 cells. The expressions of apoptosis-related proteins (Bcl-2, Bax, and cleaved caspase-3) and autophagy-related proteins (P62 and Beclin-1) in the treated cells were detected using Western blotting. DDP increased the expression of IL-17RA in ovarian cancer SKOV3 cells. Treatment with IL-17A significantly reduced the susceptibility of SKOV3 cells to cisplatin-induced apoptosis (P < 0.05). DDP obviously augmented the expression of Beclin-1 and reduced the autophagy degradation substrate P62 protein in the cells (P < 0.05). IL-17A/IL-17RA strongly enhanced the DDPinducted autophagy of the cells (P < 0.05). Blocking autophagy with 3-MA significantly increased DDP- induced apoptosis of SKOV3 cells with IL-17RA silencing, lowered the expression of Bcl-2 and enhanced Bax expression in the cells (P < 0.05). IL-17A/IL-17RA can decrease chemosensitivity of SKOV3 cells to DDP by upregulating DDP-induced autophagy.

MiR‑576‑3p overexpression enhances cisplatin sensitivity of ovarian cancer cells by dysregulating PD‑L1 and cyclin D1.

Cisplatin (DDP) resistance is a major obstacle in the chemotherapeutic efficacy of ovarian cancer. The present study aimed to explore the role of miR‑576‑3p in DDP sensitivity of ovarian cancer cells. Ovarian cancer cell lines SKOV3 and A2780 and DDP‑resistant ovarian cancer cell lines SKOV3/DDP and A2780/DDP were used in the present study. Invitro studies demonstrated that microRNA (miR)‑576‑3p overexpression increased the DDP sensitivity of DDP‑resistant ovarian cancer cells. A dual‑luciferase assay verified that both programmed death‑ligand 1 (PD‑L1) and cyclin D1 were targets of miR‑276‑3p and were reversely associated with the expression of miR‑576‑3p. Moreover, invivo studies indicated that tumorigenesis was inhibited by DDP, which was enhanced by further miR‑576‑3p overexpression in tumor tissues. Taken together, the results suggested that miR‑576‑3p overexpression increased DDP chemosensitivity of ovarian cancer cells via decreasing PD‑L1 and cyclin D1, indicating that miR‑576‑3p may serve as a promising therapeutic target for ovarian cancer.

Dihydrotanshinone I inhibits ovarian cancer cell proliferation and migration by transcriptional repression of PIK3CA gene.

Dihydrotanshinone I (DHTS), extracted from Salvia miltiorrhiza, was found to be the most effective compound of tanshen extracts against cancer cells in our previous studies. However, the therapeutic benefits and underlying mechanisms of DHTS on ovarian cancer remain uncertain. In this study, we demonstrated the cytocidal effects of DHTS on chemosensitive ovarian cancer cells with or without platinum‐based chemotherapy. DHTS was able to inhibit proliferation and migration of ovarian cancer cells in vitro and in vivo through modulation of the PI3K/AKT signalling pathways. Combinatorial treatment of DHTS and cisplatin exhibited enhanced DNA damage in ovarian cancer cells. Overall, these findings suggest that DHTS induces ovarian cancer cells death via induction of DNA damage and inhibits ovarian cancer cell proliferation and migration.

Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity.

Cisplatin is a widely used drug in the treatment of various solid tumors, such as ovarian cancer. However, while the acquired resistance significantly limits the success of therapy, some tumors, such as colorectal cancer, are intrinsically insensitive to cisplatin. Only a small amount of intracellular platinum binds to the target—genomic DNA. The fate of the remaining drug is largely obscure. This work aimed to identify the cytosolic protein binding partners of cisplatin in ovarian and colorectal cancer cells and to evaluate their relevance for cell sensitivity to cisplatin and oxaliplatin. Using the fluorescent cisplatin analog BODIPY-cisplatin, two-dimensional gel electrophoresis, and mass spectrometry, we identified the protein binding partners in A2780 and cisplatin-resistant A2780cis ovarian carcinoma, as well as in HCT-8 and oxaliplatin-resistant HCT-8ox colorectal cell lines. Vimentin, only identified in ovarian cancer cells; growth factor receptor-bound protein 2, only identified in colorectal cancer cells; and glutathione-S-transferase π, identified in all four cell lines, were further investigated. The effect of pharmacological inhibition and siRNA-mediated knockdown on cytotoxicity was studied to assess the relevance of these binding partners. The silencing of glutathione-S-transferase π significantly sensitized intrinsically resistant HCT-8 and HCT-8ox cells to cisplatin, suggesting a possible involvement of the protein in the resistance of colorectal cancer cells to the drug. The inhibition of vimentin with FiVe1 resulted in a significant sensitization of A2780 and A2780cis cells to cisplatin, revealing new possibilities for improving the chemosensitivity of ovarian cancer cells.

Extracellular biophysical environment: Guilty of being a modulator of drug sensitivity in ovarian cancer cells

The roles of the extracellular biophysical environment in cancer are barely studied. This study considers the possibility that cell-like topography of a cancer cell environment may influence chemo-responses. Here, a novel bioimprinting technique was employed to produce cell-like topography on the polystyrene substrates used for cell culture. In this work, we have shown that extracellular biophysical cues generated from the topography alter the chemosensitivity of ovarian cancer cells. The three-dimensionality of the bioimprinted surface altered the cell-surface interaction, which consequently modulated intracellular signalling and chemoresponses. Sensitivity to platinum was altered more than that to paclitaxel. The effect was largely mediated through the integrin/focal adhesion system and the Rho/ROCK pathway. Moreover, the results provided evidence that biophysical cues also modulate MAPK signalling associated with chemo-resistance in ovarian cancer. Therefore, the novel findings from of this study revealed for the first time that the effects of the biophysical environment, such as substrate topography, influences ovarian cancer cell responses to clinical drugs. These observations suggest that a full clinical understanding of ovarian cancer will include biophysical aspects of tumour microenvironment.

In silico analysis of DYNLL1 expression in ovarian cancer chemoresistance.

Ovarian cancer (OC) is the most lethal gynecological cancer and chemoresistance is responsible for the treatment failure and unfavorable clinical outcome in this disease. The deletion of DYNLL1 was reported to result in increased chemoresistance in BRCA1-mutant high-grade serous ovarian carcinoma cells. Considering its role in chemoresistance, a better understanding of DYNLL1 expression is needed to develop novel strategies in the treatment of OC. In the current study, we aimed to investigate the differential expression of DYNLL1 in OC with respect to cell types, chemosensitivity profiles, certain drug treatments, and cancer progression. DYNLL1 levels were analyzed using expression profiling data sets from Gene Expression Omnibus and quantitative reverse-transcription polymerase chain reaction in R. We found that the level of DYNLL1 was higher in OC histotypes compared with normal ovarian cells. DYNLL1 expression is decreased in OC cells of epithelial type; but, it is increased in OC cells of stromal type, compared with matched control cells. Chemoresistant OC cells were shown to have lower DYNLL1 expression than chemosensitive OC cells. Carboplatin and NSC319726 treatments resulted in slightly decreased DYNLL1 expression and DYNLL1 levels were decreased in the course of cancer progression in OC epithelial cells. The results suggest that changes in DYNLL1 expression in OC might be cell-type dependent and lower DYNLL1 levels may be associated with increased chemoresistance in OC. Although further studies are needed, certain drugs and cancer progression may lead to lower DYNLL1 levels, possibly resulting in increased chemoresistance. Therefore, it can be stated that DYNLL1 might be an important player in OC progression and chemoresistance.

PLAG1 silencing promotes cell chemosensitivity in ovarian cancer via the IGF2 signaling pathway.

Ovarian cancer (OC) is one of the most lethal gynecological diseases. Novel prognostic biomarkers and therapeutic targets for OC are urgently required. The aim of this study was to investigate the mechanisms that govern how pleomorphic adenoma gene 1 (PLAG1) influences the biological processes and chemosensitivity of OC cells via the insulin-like growth factor-2 (IGF2) signaling pathway. Differentially expressed genes in OC were selected based on bioinformatics data. OC and adjacent tissue specimen were collected, followed by the determination of the expression of PLAG1 and IGF2 signaling pathway-associated genes. The regulatory mechanisms of PLAG1 in OC cells were analyzed following treatment with pcDNA or small interfering RNA (siRNA), and included the assessment of cell proliferation, migration, invasion and cisplatin resistance. PLAG1 was identified as an upregulated gene in OC. OC tissues exhibited increased expression of PLAG1 and IGF2 compared with the controls. Moreover, PLAG1 was observed to positively regulate the IGF2 signaling pathway. The siRNA-mediated silencing of PLAG1 resulted in decreased expression of IGF2, IGF1 receptor and insulin receptor substrate 1, as well as inhibited proliferation, migration, invasion and cisplatin resistance of OC cells. Furthermore, the effect of PLAG1 was dependent on IGF2. PLAG1 may therefore be considered as a possible target for the treatment of OC.

The exosome-mediated autocrine and paracrine actions of plasma gelsolin in ovarian cancer chemoresistance

Ovarian cancer (OVCA) is the most lethal gynecological cancer, due predominantly to late presentation, high recurrence rate and common chemoresistance development. The expression of the actin-associated protein cytosolic gelsolin (GSN) regulates the gynecological cancer cell fate resulting in dysregulation in chemosensitivity. In this study, we report that elevated expression of plasma gelsolin (pGSN), a secreted isoform of GSN and expressed from the same GSN gene, correlates with poorer overall survival and relapse-free survival in patients with OVCA. In addition, it is highly expressed and secreted in chemoresistant OVCA cells than its chemosensitive counterparts. pGSN, secreted and transported via exosomes (Ex-pGSN), upregulates HIF1α–mediated pGSN expression in chemoresistant OVCA cells in an autocrine manner as well as confers cisplatin resistance in otherwise chemosensitive OVCA cells. These findings support our hypothesis that exosomal pGSN promotes OVCA cell survival through both autocrine and paracrine mechanisms that transform chemosensitive cells to resistant counterparts. Specifically, pGSN transported via exosomes is a determinant of chemoresistance in OVCA.

Inhibition LC3B can increase chemosensitivity of ovarian cancer cells

BackgroundOvarian cancer is often accompanied by the production of ascites, and patients with repeated ascites are associated with chemotherapy resistance. The previous study confirmed that the ovarian cancer patients who developed ascites after chemotherapy had elevated autophagy levels in the ascites and precipitated cells, which was positively correlated with MDR1 expression in the blood of patients.MethodsIn order to explore the correlation between autophagy and chemoresistant, we searched TCGA and GEO database to analyze the correlation between LC3B and MDR1, and identified the targeting miRNA of LC3B. It was verified by dual luciferase that miR-204 can target LC3B. The ovarian cancer cell line and the BALB/c nude mice tumor-bearing model were selected for in vitro and in vivo verification. In vitro studies confirmed that ovarian cancer cells were more sensitive to cisplatin by inhibiting LC3B.ResultsOverexpression of miR-204 reduced the expression of LC3B, Atg7, and MDR1, and promoted apoptosis. In vivo studies have also confirmed that reducing the level of autophagy in ovarian cancer cells increases the sensitivity to cisplatin.ConclusionsIt suggests that miR-204 can be used as a tumor suppressor gene and LC3B expression level can be used as a potential molecular marker to guide the diagnosis and treatment of patients with ovarian cancer.

Acylated Ghrelin Renders Chemosensitive Ovarian Cancer Cells Resistant to Cisplatin Chemotherapy via Activation of the PI3K/Akt/mTOR Survival Pathway

This study investigated the effect of acylated synthetic ghrelin (AG) on the survival and proliferation of human chemosensitive ovarian cancer cells (A2780) and explored some mechanisms of action with a focus on the p53 apoptotic pathway and PI3K/Akt and NF-κB survival pathways. Human A2780 ovarian cancer cells were cultured with or without AG treatment in the presence or absence of cisplatin. In some cases, cisplatin+AG-treated cells were pre-incubated either with [D-Lys3]-GHRP-6, a ghrelin receptor antagonist, or with LY294002, a PI3K inhibitor. mRNA of ghrelin receptors(GHS-R1a and GHS-R1b), as well as, protein levels of GHS-R1a, were expressed abundantly in A2780 cells. AG treatment did not affect the mRNA and protein levels of GHS-R1a and GHS-R1b in both control and Cis-treated cells. However, while AG treatment had no effect on control cell viability, it significantly increased cell viability and proliferation and inhibited cell death in Cis-treated cells. In both control and Cis-treated cells, AG treatment significantly increased PI3K/Akt/mTOR signaling and enhanced the nuclear accumulation of NF-κB. Concomitantly, in both control and Cis-treated cells, AG significantly lowered the protein levels of p53, p-p53 (Ser16), PUMA, cytochrome C, and cleaved caspase-3. Interestingly, pre-incubating the cells with either [D-Lys3]-GHRP-6 or LY294002 completely abolished the above-mentioned effect of AG in both control and Cis-treated cells. In conclusion, the findings of this study show that AG promotes cell survival of the OC cells and renders them resistat to Cis therapy, an effect that is mediated by the activation of PI3K/Akt/mTOR and activation of NF-κB, and requires GHS-R1a.