Chemotherapy Resistance In Ovarian Cancer Research Articles

Delivery of doxorubicin by Fe3O4 nanoparticles, reduces multidrug resistance gene expression in ovarian cancer cells

BackgroundOvarian cancer is one of the most common malignancy in women with significant mortality rate due to the resistance to chemotherapy drugs. Doxorubicin (DOX) is a chemotropic agent in ovarian cancer treatment. Overexpression of multidrug resistance (MDR) genes, such as ABCB1, in cancer cells after chemotherapy is one of main problems in clinical applications. Here we have compared the efficiency of doxorubicin-loaded (NIPAAM-DMAEMA) Fe3O4 nanocomposite (DOX-NANO) against DOX on ABCB1(MDR1) gene expression in the ovarian cancer cell line. Materials and MethodsThe cell viability of SKOV-3 cells were evaluated by MTT assay. Real Time PCR was used to measure the expression level of MDR1. MTT data were normalized in 10 different attribute weighting models, also to reveal the interaction between DOX, ABCB1, and ovarian cancer genes, Pathway Studio Database (Elsevier) was used. ResultsCell viability of SKOV-3cells was significantly decreased after 24, 48 and 72hours (P < 0.0001) of either DOX with IC50 22.38, 0.61 and 0.072µg/ml or DOX-NANO treatment with IC50 11.54, 1.01, 0.0126µg/ ml respectively. treatment. Notable decrease in the expression of MDR gene, ABCB1, was observed 48hours after treatment with DOX-NANO (P < 0.0001) with 26% in the assessed with control group. Meta-analysis showed the concentration of 10μg/ml variables was the second most significant feature, whereas the concentration of 0.01μg/ml recognized the lowest weights. Also, LGALS3 is an extra cellular receptor with upregulation in ovarian cancer that interacts with ABCB1. ConclusionOur findings highlight the beneficial effects of DOX delivery in ovarian cancer cells by nanocomposite as efficient drug delivery method. DOX-NANO is a promising therapeutic reagent to overcome chemotherapy resistance in ovarian cancer.

Immune escape between endoplasmic reticulum stress-related cancer cells and exhausted CD8+T cells leads to neoadjuvant chemotherapy resistance in ovarian cancer

Our study aims to explore the effects of neoadjuvant chemotherapy (NACT) on tumour cells and immune cells in the immune microenvironment of patients with high-grade serous ovarian cancer (HGSOC).Single-cell RNA sequencing data of paired ovarian cancer tissues were analysed before and after NACT in 11 patients with HGSOC. The effect of NACT on two major cell components of the tumour microenvironment, epithelial cells and CD8+T cells, was investigated. The mechanisms of epithelial cell evasion by NACT and immune killing were explored from the perspectives of gene expression, functional characteristics, transcriptional regulation, and cell communication. Key targets for reversing NACT resistance were identified and possible therapeutic strategies proposed.While NACT improved the de novo differentiation of anti-tumour CD8+T cells, enhancing their anti-tumour function, it increased the proportion of cancer cells with high HSP90B1 expression. Thus, the potential reasons for NACT resistance were identified as: 1) high levels of endoplasmic reticulum stress (ERS) characteristics, 2) high expression of the MDK-NCL ligand-receptor pair between them and exhausted CD8+T cells before NACT, and 3) high expression of the NECTIN2-TIGIT immune ligand-receptor pair between them and exhausted CD8+T cells after NACT.Thus, our study reveals the mechanisms underlying NACT resistance in patients with HGSOC from the perspective of the independent and interactive roles of cancer cells and CD8+T cells. We propose therapeutic strategies targeting the ERS marker HSP90B1 and the immune escape marker MDK before or during NACT, while targeting NECTIN2 blockade after NACT. This approach may offer new insights into combination treatments for patients with HGSOC displaying NACT resistance.

CRLF1 bridges AKT and mTORC2 through SIN1 to inhibit pyroptosis and enhance chemo-resistance in ovarian cancer

Ovarian cancer, the second most leading cause of gynecologic cancer mortality worldwide, is challenged by chemotherapy resistance, presenting a significant hurdle. Pyroptosis, an inflammation-linked programmed cell death mediated by gasdermins, has been shown to impact chemoresistance when dysregulated. However, the mechanisms connecting pyroptosis to chemotherapy resistance in ovarian cancer are unclear. We found that cytokine receptor-like factor 1 (CRLF1) is a novel component of mTORC2, enhancing AKT Ser473 phosphorylation through strengthening the interaction between AKT and stress-activated protein kinase interacting protein 1 (SIN1), which in turn inhibits the mitogen-activated protein kinase kinase kinase 5 (ASK1)-JNK-caspase-3-gasdermin E pyroptotic pathway and ultimately confers chemoresistance. High CRLF1-expressing tumors showed sensitivity to AKT inhibition but tolerance to cisplatin. Remarkably, overexpression of binding-defective CRLF1 variants impaired AKT-SIN1 interaction, promoting pyroptosis and chemosensitization. Thus, CRLF1 critically regulates chemoresistance in ovarian cancer by modulating AKT/SIN1-dependent pyroptosis. Binding-defective CRLF1 variants could be developed as tumor-specific polypeptide drugs to enhance chemotherapy for ovarian cancer.

Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer

Background Ovarian cancer management has not yet given a satisfactory result, and the recurrence rate is still high. One of the reasons for this is resistance to chemotherapy. Melatonin and cisplatin may be involved in the chemotherapy resistance of ovarian cancer. Methods A laboratory experiment was performed using melatonin and cisplatin in the SKOV3 cell, from September 2020 to November 2021 at the SCTE and Integrated Laboratory &amp; Research Center Universitas Indonesia. Several variables were used, such as doxorubicin, melatonin, cisplatin, and combination of cisplatin and melatonin at several concentrations (1×, 3/4×, 1/2×, and 1/4×). A total of 24 samples were included and divided into 8 groups. The IC50 values of melatonin, doxorubicin, and cisplatin as well as cell viability was calculated via MTS assay. Subsequently, flow cytometry was performed to assess the effect of cisplatin and melatonin on the mechanisms of CTR1, p-glycoprotein, GSH, ERCC1, e-cadherin, and apoptosis. Analysis of variance and Bonferroni test were employed for the study. Results The IC50 values of melatonin, cisplatin, and doxorubicin were 1.841 mM, 117.5 mM, and 14.72 mM, respectively. The combination groups of cisplatin and melatonin reduced cell viability; decreased the CTR1 mean (19.73), Pgp (6.7), GSH (11.73), and ERCC1 (4.27) in the combination 1 (C1) group; and increased e-cadherin (32.2) and annexin V (53.57) also in the combination 1 (C1) group. Conclusions The combination of melatonin and cisplatin might have an impact on drug resistance via several mechanisms in ovarian cancer.

ABT‑737 increases cisplatin sensitivity through the ROS‑ASK1‑JNK MAPK signaling axis in human ovarian cancer cisplatin‑resistant A2780/DDP cells.

Ovarian cancer is a gynecological malignant tumor with the highest mortality rate, and chemotherapy resistance seriously affects patient therapeutic outcomes. It has been shown that the high expression of anti‑apoptotic proteins Bcl‑2 and Bcl‑xL is closely related to ovarian cancer chemotherapy resistance. Therefore, reducing Bcl‑2 and Bcl‑xL expression levels may be essential for reversing drug resistance in ovarian cancer. ABT‑737 is a BH3‑only protein mimetic, which can effectively inhibit the expression of the anti‑apoptotic proteins Bcl‑xL and Bcl‑2. Although it has been shown that ABT‑737 can increase the sensitivity of ovarian cancer cells to cisplatin, the specific molecular mechanism remains unclear and requires further investigation. In the present study, the results revealed that ABT‑737 can significantly increase the activation levels of JNK and ASK1 induced by cisplatin in A2780/DDP cells, which are cisplatin‑resistant ovarian cancer cells. Inhibition of the JNK and ASK1 pathway could significantly reduce cisplatin cytotoxicity increased by ABT‑737 in A2780/DDP cells, while inhibiting the ASK1 pathway could reduce JNK activation. In addition, it was further determined that ABT‑737 could increase reactive oxygen species (ROS) levels in A2780/DDP cells induced by cisplatin. Furthermore, the inhibition of ROS could significantly reduce JNK and ASK1 activation and ABT‑737‑mediated increased cisplatin cytotoxicity in A2780/DDP cells. Overall, the current data identified that activation of the ROS‑ASK1‑JNK signaling axis plays an essential role in the ability of ABT‑737 to increase cisplatin sensitivity in A2780/DDP cells. Therefore, upregulation the ROS‑ASK1‑JNK signaling axis is a potentially novel molecular mechanism by which ABT‑737 can enhance cisplatin sensitivity of ovarian cancer cells. In addition, the present research can also provide new therapeutic strategies and new therapeutic targets for patients with cisplatin‑resistant ovarian cancer with high Bcl‑2/Bcl‑xL expression patterns.

Single-cell transcriptome analysis of macrophage subpopulations contributing to chemotherapy resistance in ovarian cancer

BackgroundOvarian cancer, a fatal gynecological malignancy, is primarily managed through surgery and chemotherapy. However, a significant challenge arises as patients frequently experience relapse due to chemotherapy resistance. This study delves into the complex functions and underlying mechanisms of macrophages in chemotherapy resistance in ovarian cancer. MethodThe single-cell transcriptome sequencing data of ovarian cancer with or without chemotherapy were analyzed. Then, corresponding cell types were identified, and macrophages were extracted from all cells. Following the standardized single-cell analysis using the Seurat package, 15 distinct macrophage clusters were found and differentially expressed genes among them were analyzed. Moreover, their association with chemotherapy resistance was explored through cell proportions and gene expression. ResultIn the single-cell transcriptomic analysis of ovarian cancer tissues before and after chemotherapy, the cellular proportion of CXCL5+ macrophages, THBS1+ macrophages, and MMP9+ macrophages were significantly increased following chemotherapy. Further investigation revealed that these macrophage subpopulations upregulated the expression of multiple pro-tumorigenic angiogenic or invasive factors, in addition to CXCL5, THBS1, and MMP9, including CTSL, CXCL1, and CCL18. Finally, pathway enrichment analysis revealed the significant activation of signaling pathways, such as NOD-like receptor, MAPK, and TNF in these macrophage subpopulations, which provides direction for studying the mechanism of these subpopulations. ConclusionCXCL5+, THBS1+, and MMP9+ macrophage subpopulations exhibit an increased cellular prevalence post-chemotherapy and pro-tumorigenic molecular expression profiles, suggesting a close association with chemoresistance in ovarian cancer. These findings contribute to our understanding of the roles and mechanisms of macrophages in ovarian cancer chemoresistance, providing a theoretical basis and direction for the development of therapies targeting macrophages in overcoming ovarian cancer chemoresistance.

ANGPTL3 diminishes the resistance of ovarian cancer to paclitaxel by blocking the PI3K-AKT-mTOR signaling pathway

Angiopoietin-like protein 3 (ANGPTL3) is key in ovarian cancer (OC) cell growth and metastasis, notably by enhancing natural killer cells' capacity for inducing cell toxicity and apoptosis. However, its role in influencing chemotherapy resistance in OC remains ambiguous. In this study, we discovered a correlation between reduced ANGPTL3 levels and a less favorable outcome in OC patients using the Kaplan-Meier Plotter database. Lower levels of ANGPTL3 were detected in paclitaxel (PTX)-resistant OC tissues and cell lines via western blotting and immunohistochemistry. To investigate ANGPTL3's effects, we established SKOV3/PTX and 2780/PTX as PTX-resistant OC cell lines by incrementally increasing PTX exposure and then transfecting them with overexpress ANGPTL3 (OE-ANGPTL3) lentivirus. We conducted various assays such as CCK-8, colony formation, Edu staining, flow cytometry, and transwell to investigate the impact of ANGPTL3 on PTX resistance. Additionally, this effect was examined in a mouse subcutaneous xenograft model. Both in vitro and in vivo experiments demonstrated that ANGPTL3 overexpression mitigated PTX resistance in OC cells by inactivating the PI3K-AKT-mTOR pathway. In summary, our research reveals that ANGPTL3 enhances PTX sensitivity in OC by downregulating the PI3K-AKT-mTOR pathway. The study of this study suggest that ANGPTL3 could serve as a valuable therapeutic target for OC, signifying its clinical relevance in OC management.

MAP7 drives EMT and cisplatin resistance in ovarian cancer via wnt/β-catenin signaling

MethodsOur approach encompasses analyzing MAP7's expression levels across various datasets and clinical specimens, evaluating its association with patient outcomes, and probing its influence on ovarian cancer cell dynamics such as proliferation, migration, invasion, and apoptosis. ResultsWe have identified significant upregulation of MAP7 in ovarian cancer tissues, which correlates with advanced disease stages, higher pathological grades, and unfavorable prognoses. Functionally, the inhibition of MAP7 suppresses cancer cell proliferation, migration, and invasion while promoting apoptosis. Notably, the silencing of MAP7 attenuates the epithelial-mesenchymal transition (EMT) and disrupts Wnt/β-catenin pathway signaling—two critical processes implicated in metastasis and chemoresistance. In cisplatin-resistant A2780-DDP cells, the downregulation of MAP7 effectively reverses their resistance to cisplatin. Furthermore, the nuclear localization of MAP7 in these cells underscores its pivotal role in driving cisplatin resistance by modulating the transcriptional regulation and interaction dynamics of β-catenin. ConclusionOur findings position MAP7 as a pivotal element in ovarian cancer advancement and cisplatin resistance, primarily through its modulation of EMT and the Wnt/β-catenin pathway. Its association with poor clinical outcomes underscores its potential as both a prognostic marker and a therapeutic target. Strategies aimed at MAP7 could represent a new frontier in combating chemotherapy resistance in ovarian cancer, emphasizing its significance in crafting complementary treatments for this disease.

"Long-Term Cryopreservation of an Autologous Immunocomplex of Dendritic Cells and Cancer Antigen (HiDCV-OS1) that Stimulates Antitumor Immunity Against Chemotherapy-Resistant Ovarian Cancer"

"Long-Term Cryopreservation of an Autologous Immunocomplex of Dendritic Cells and Cancer Antigen (HiDCV-OS1) that Stimulates Antitumor Immunity Against Chemotherapy-Resistant Ovarian Cancer"

Machine learning developed a fibroblast-related signature for predicting clinical outcome and drug sensitivity in ovarian cancer.

Ovarian cancer (OC) is the leading cause of gynecological cancer death. Cancer-associated fibroblasts (CAF) is involved in wound healing and inflammatory processes, tumor occurrence and progression, and chemotherapy resistance in OC. GSE184880 dataset was used to identify CAF-related genes in OC. CAF-related signature (CRS) was constructed using integrative 10 machine learning methods with the datasets from the Cancer Genome Atlas, GSE14764, GSE26193, GSE26712, GSE63885, and GSE140082. The performance of CRS in predicting immunotherapy benefits was verified using 3 immunotherapy datasets (GSE91061, GSE78220, and IMvigor210) and several immune calculating scores. The Lasso + StepCox[forward] method-based predicting model having a highest average C index of 0.69 was referred as the optimal CRS and it had a stable and powerful performance in predicting clinical outcome of OC patients, with the 1-, 3-, and 5-year area under curves were 0.699, 0.708, and 0.767 in the Cancer Genome Atlas cohort. The C index of CRS was higher than that of tumor grade, clinical stage, and many developed signatures. Low CRS score demonstrated lower tumor immune dysfunction and exclusion score, lower immune escape score, higher PD1&CTLA4 immunophenoscore, higher tumor mutation burden score, higher response rate and better prognosis in OC, suggesting a better immunotherapy response. OC patients with low CRS score had a lower half maximal inhibitory concentration value of some drugs (Gemcitabine, Tamoxifen, and Nilotinib, etc) and lower score of some cancer-related hallmarks (Notch signaling, hypoxia, and glycolysis, etc). The current study developed an optimal CRS in OC, which acted as an indicator for the prognosis, stratifying risk and guiding treatment for OC patients.

Abstract 6320: CAR-T cells targeting LGR5: An effective treatment for chemotherapy resistant ovarian cancer

Abstract Ovarian cancer is the second leading cause of cancer-related mortality among gynaecological cancers in the Western world. CAR-T cell therapy is an adoptive immunotherapy used to treat some blood cancers. This study has investigated whether leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a suitable target for CAR-T cell therapy for ovarian cancer. We assessed the cytotoxic effects of LGR5-targeting CAR-T cells on a range of ovarian cancer cell lines and primary serous ovarian cancer cells derived from patient ascites (at diagnosis and following relapse with chemotherapy resistant disease) in monolayer culture, 3D spheroid assays and patient-derived explant assays. OVCAR3 and a chemoresistant patient-derived xenograft (PDX) models have been used to assess whether LGR5-targeting CAR-T cells can inhibit growth and metastasis in vivo. We found that LGR5 is highly expressed in high-grade serous ovarian carcinoma (HGSOC) cancer cell lines and LGR5 expression was increased in chemotherapy resistant primary ovarian cancer cells. We demonstrated that LGR5-targeting CAR-T cells were cytotoxic and significantly inhibited the survival of ovarian cancer cell lines and chemotherapy-resistant primary ovarian cancer cells with high LGR5 expression levels in both monolayer culture and 3D spheroids compared to un-transduced CD3+ T cells. In patient-derived explant assays, we observed increased apoptosis in HGSOC tissues expressing high LGR5 following treatment with LGR5-targeting CAR-T cells. In vivo, LGR5-targeting CAR-T cell treatment decreased the tumour burden in mice with OVCAR3 xenografts and a chemotherapy-resistant PDX model with high LGR5 expression, compared to CD3+ T cells. In summary, LGR5-targeting CAR-T cells have great potential to be developed as a novel immunotherapy for ovarian cancer. Citation Format: Wanqi (Jady) Wang, Veronika Bandara, Noor A. Lokman, Zoe K K. Price, Tannith M. Noye, Silvana Napoli, Batjargal Gundsambuu, Martin K. Oehler, Simon C. Barry, Carmela Ricciardelli. CAR-T cells targeting LGR5: An effective treatment for chemotherapy resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6320.

Abstract 4318: CD24 enhances cisplatin resistance in ovarian cancer by suppressing autophagy

Abstract Ovarian cancer is one of the most common gynecological cancers with the highest mortality rate. Most patients are diagnosed with advanced disease and will relapse due to chemoresistance. CD24, a highly glycosylated GPI-anchored membrane protein. Recent studies have shown that CD24 expression is significantly up-regulated in ovarian cancer and is associated with chemotherapy resistance, and CD24 also plays an inhibitory role in tumor immunity by binding to Siglec-10 on macrophages. However, the molecular mechanisms of how CD24 affects chemotherapy resistance in ovarian cancer remain unclear. In this study, we used shRNAs to knockdown CD24 and explore the impact and mechanism of CD24 on the chemotherapy resistance of ovarian cancer cells. The results showed that knockdown of CD24 in ovarian cancer cells SKOV3 and TOV21G significantly reduced cell proliferation and arrested the cell cycle in S phase. Knockdown of CD24 also significantly increased the sensitivity of ovarian cancer cells to cisplatin but had no effect on paclitaxol treatment. Further experiments showed that knockdown of CD24 increased cisplatin sensitivity by promoting autophagy-induced cell death. In addition, Gene Set Enrichment Analysis (GSEA) was used to analyze the correlation between the expression of CD24 and its biological functions in the TCGA ovarian cancer dataset. The results showed that CD24 is mostly correlated to cell proliferation and autophagy-related pathways in ovarian cancers. Further mouse xenograft tumor transplantation experiments also confirmed that knockdown of CD24 reduced tumor size and increased sensitivity to cisplatin treatment by increasing cell autophagy. Taken together, these results indicate that CD24 regulates cell growth and chemoresistance in ovarian cancer cells and that inhibition of CD24 may be helpful in the treatment of ovarian cancer. Citation Format: Yuh-Ling Chen, Tse-Ming Hong, Yu-Yi Wen. CD24 enhances cisplatin resistance in ovarian cancer by suppressing autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4318.

STING inhibitors sensitize platinum chemotherapy in ovarian cancer by inhibiting the CGAS-STING pathway in cancer-associated fibroblasts (CAFs)

Chemotherapy resistance in ovarian cancer hampers cure rates, with cancer-associated fibroblasts (CAFs) playing a pivotal role. Despite their known impact on cancer progression and chemotherapy resistance, the specific mechanism by which CAFs regulate the tumor inflammatory environment remains unclear. This study reveals that cisplatin facilitates DNA transfer from ovarian cancer cells to CAFs, activating the CGAS-STING-IFNB1 pathway in CAFs and promoting IFNB1 release. Consequently, this reinforces cancer cell resistance to platinum drugs. High STING expression in the tumor stroma was associated with a poor prognosis, while inhibiting STING expression enhanced ovarian cancer sensitivity. Understanding the relevance of the CGAS-STING pathway in CAFs for platinum resistance suggests targeting STING as a promising combination therapy for ovarian cancer, providing potential avenues for improved treatment outcomes.

Promising effect of cisplatin and melatonin combination on the inhibition of cisplatin resistance in ovarian cancer

Background Ovarian cancer management has not yet given a satisfactory result, and the recurrence rate is still high. One of the reasons for this is resistance to chemotherapy. Melatonin and cisplatin may be involved in the chemotherapy resistance of ovarian cancer. Methods A laboratory experiment was performed using melatonin and cisplatin in the SKOV3 cell, from September 2020 to November 2021 at the SCTE and Integrated Laboratory &amp; Research Center Universitas Indonesia. Several variables were used, such as doxorubicin, melatonin, cisplatin, and combination of cisplatin and melatonin at several concentrations (1×, 3/4×, 1/2×, and 1/4×). A total of 24 samples were included and divided into 8 groups. The IC50 values of melatonin, doxorubicin, and cisplatin as well as cell viability was calculated via MTS assay. Subsequently, flow cytometry was performed to assess the effect of cisplatin and melatonin on the mechanisms of CTR1, p-glycoprotein, GSH, ERCC1, e-cadherin, and apoptosis. Analysis of variance and Bonferroni test were employed for the study. Results The IC50 values of melatonin, cisplatin, and doxorubicin were 1.841 mM, 117.5 mM, and 14.72 mM, respectively. The combination groups of cisplatin and melatonin reduced cell viability; decreased the CTR1 mean (19.73), Pgp (6.7), GSH (11.73), and ERCC1 (4.27) in the combination 1 (C1) group; and increased e-cadherin (32.2) and annexin V (53.57) also in the combination 1 (C1) group. Conclusions The combination of melatonin and cisplatin might have an impact on drug resistance via several mechanisms in ovarian cancer.

Reversal of Platinum-based Chemotherapy Resistance in Ovarian Cancer by Naringin Through Modulation of The Gut Microbiota in a Humanized Nude Mouse Model.

As a chemotherapy agent, cisplatin (DDP) is often associated with drug resistance and gastrointestinal toxicity, factors that severely limit therapeutic efficacy in patients with ovarian cancer (OC). Naringin has been shown to increase sensitivity to cisplatin, but whether the intestinal microbiota is associated with this effect has not been reported so far. In this study, we applied a humanized mouse model for the first time to evaluate the reversal of cisplatin resistance by naringin, as well as naringin combined with the microbiota in ovarian cancer. The results showed that naringin combined with Bifidobacterium animalis subsp. lactis NCU-01 had an inhibitory effect on the tumor, significantly reducing tumor size (p<0.05), as well as the concentrations of serum tumor markers CA125 and HE4, increased the relative abundance of Bifidobacterium and Bacteroides, inhibit Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB)-induced intestinal inflammation and increase the expression of intestinal permeability-associated proteins ZO-1 (p<0.001) and occludin (p<0.01). In conclusion, the above data demonstrate how naringin combined with Bifidobacterium animalis subsp. lactis NCU-01 reverses cisplatin resistance in ovarian cancer by modulating the intestinal microbiota, inhibiting the TLR4/NF-κB signaling pathway and modulating the p38MAPK signaling pathway.

Effective sequential combined therapy with carboplatin and a CDC7 inhibitor in ovarian cancer

BackgroundThe enhancement of DNA damage repair is one of the important mechanisms of platinum resistance. Protein cell division cycle 7 (CDC7) is a conserved serine/threonine kinase that plays important roles in the initiation of DNA replication and is associated with chemotherapy resistance in ovarian cancer. However, whether the CDC7 inhibitor XL413 has antitumor activity against ovarian cancer and its relationship with chemosensitivity remain poorly elucidated. MethodsWe evaluated the antitumor effects of carboplatin combined with XL413 for ovarian cancer in vitro and in vivo. Cell viability inhibition, colony formation and apoptosis were assessed. The molecules related to DNA repair and damage were investigated. The antitumor effects of carboplatin combined with XL413 were also evaluated in SKOV-3 and OVCAR-3 xenografts in subcutaneous and intraperitoneal tumor models. ResultsSequential administration of XL413 after carboplatin (CBP) prevented cellular proliferation and promoted apoptosis in ovarian cancer (OC) cells. Compared with the CBP group, the expression level of RAD51 was significantly decreased and the expression level of γH2AX was significantly increased in the sequential combination treatment group. The equential combination treatment could significantly inhibit tumor growth in the subcutaneous and intraperitoneal tumor models, with the expression of RAD51 and Ki67 significantly decreased and the expression of γH2AX increased. ConclusionsSequential administration of CDC7 inhibitor XL413 after carboplatin can enhance the chemotherapeutic effect of carboplatin on ovarian cancer cells. The mechanism may be that CDC7 inhibitor XL413 increases the accumulation of chemotherapy-induced DNA damage by inhibiting homologous recombination repair activity.

Zinc oxide nanoparticles inhibit malignant progression and chemotherapy resistance of ovarian cancer cells by activating endoplasmic reticulum stress and promoting autophagy.

The mortality rate of ovarian cancer (OC) is high, posing a serious threat to women's lives. Zinc oxide nanoparticles (ZnO-NPs) show great potential in the treatment of cancer. However, the mechanism of ZnO-NPs in inhibiting the malignant proliferation and chemotherapy resistance of OC has remained elusive. In the present study, ZnO-NPs at different concentrations were used to treat SKOV3 cells, and subsequently, analyses including the Cell Counting Kit-8 assay, EDU staining, colony-formation assay, flow cytometry, wound-healing assay, Transwell assay and western blot were used to detect cell proliferation, invasion, migration, epithelial-mesenchymal transition (EMT) and chemotherapy resistance, as well as endoplasmic reticulum stress (ERS)- and autophagy-related indicators. Finally, the mechanisms of action of ZnO-NPs on OC were examined by adding ERS inhibitor 4-phenylbutyric acid (4-PBA) and autophagy inhibitor 3-methyladenine (3-MA). It was found that ZnO-NPs inhibited SKOV3 cell proliferation, facilitated apoptosis and induced cell cycle arrest. Furthermore, ZnO-NPs inhibited the invasion, migration and EMT of SKOV3 cells. ZnO-NPs also inhibited chemotherapy resistance of SKOV3 cells. ZnO-NPs activated ERS and promoted autophagy. The addition of 4-PBA or 3-MA significantly reversed the effects of ZnO-NPs on SKOV3 cells. Overall, ZnO-NPs inhibit the malignant progression and the chemotherapy resistance of SKOV3 cells by activating ERS and promoting autophagy.

CircSLC39A8 attenuates paclitaxel resistance in ovarian cancer by regulating the miR‑185‑5p/BMF axis

Chemoresistance to paclitaxel (PTX) is one of the main reasons for treatment failure and poor prognosis in patients with advanced ovarian cancer. Therefore, it is imperative to explore the mechanisms related to chemotherapy resistance in ovarian cancer to find potential therapeutic targets. Circular RNAs (circRNAs) play important roles in cancer development and progression. However, their biological functions and clinical significance in ovarian cancer have not been fully elucidated. Therefore, in this study, we aimed to investigate the function and underlying mechanism of hsa_circ_0002782 (circSLC39A8), identified by circRNA sequencing, in regulating PTX resistance. The effects of circSLC39A8 on PTX resistance was assessed by cell viability, colony formation, flow cytometry assays and an in vivo subcutaneous xenografted tumor mouse model. RNA immunoprecipitation and dual-luciferase reporter assays were performed to verify the interaction between circSLC39A8 and the miR-185–5p/BMF signal axis. We found that circSLC39A8 was downregulated in PTX-resistant ovarian cancer cells and tissues, and its low expression was associated with poor prognosis. Biologically, circSLC39A8 knockdown promoted PTX resistance in vitro and in vivo, while circSLC39A8 overexpression showed the opposite effect. Mechanistically, circSLC39A8, acting as an endogenous sponge for miR-185–5p, could relieve the inhibition of miR-185–5p on the expression of its downstream target, BMF; thus enhancing the sensitivity of ovarian cancer to PTX. Our findings demonstrate that circSLC39A8 can promote PTX sensitivity by regulating the miR-185–5p/BMF axis. This may be a valuable prognostic biomarker and a promising therapeutic target for patients with ovarian cancer.

HMOF induces cisplatin resistance of ovarian cancer by regulating the stability and expression of MDM2

Histone acetyltransferase human males absent on the first (hMOF) is a member of MYST family which participates in posttranslational chromatin modification by controlling the acetylation level of histone H4K16. Abnormal activity of hMOF occurs in multiple cancers and biological alteration of hMOF expression can affect diverse cellular functions including cell proliferation, cell cycle progression and embryonic stem cells (ESCs) self-renewal. The relationship between hMOF and cisplatin resistance was investigated in The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) database. Lentiviral-mediated hMOF-overexpressed cells or hMOF-knockdown cells were established to investigate its role on cisplatin-based chemotherapy resistance in vitro ovarian cancer cells and animal models. Furthermore, a whole transcriptome analysis with RNA sequencing was used to explore the underlying molecular mechanism of hMOF affecting cisplatin-resistance in ovarian cancer. The data from TCGA analysis and IHC identification demonstrated that hMOF expression was closely associated with cisplatin-resistance in ovarian cancer. The expression of hMOF and cell stemness characteristics increased significantly in cisplatin-resistant OVCAR3/DDP cells. In the low hMOF expressing ovarian cancer OVCAR3 cells, overexpression of hMOF improved the stemness characteristics, inhibited cisplatin-induced apoptosis and mitochondrial membrane potential impairment, as well as reduced the sensitivity of OVCAR3 cells to cisplatin treatment. Moreover, overexpression of hMOF diminished tumor sensitivity to cisplatin in a mouse xenograft tumor model, accompanied by decrease in the proportion of cisplatin-induced apoptosis and alteration of mitochondrial apoptosis proteins. In addition, opposite phenotype and protein alterations were observed when knockdown of hMOF in the high hMOF expressing ovarian cancer A2780 cells. Transcriptomic profiling analysis and biological experimental verification orientated that MDM2-p53 apoptosis pathway was related to hMOF-modulated cisplatin resistance of OVCAR3 cells. Furthermore, hMOF reduced cisplatin-induced p53 accumulation by stabilizing MDM2 expression. Mechanistically, the increased stability of MDM2 was due to the inhibition of ubiquitinated degradation, which resulted by increased of MDM2 acetylation levels by its direct interaction with hMOF. Finally, genetic inhibition MDM2 could reverse hMOF-mediated cisplatin resistance in OVCAR3 cells with up-regulated hMOF expression. Meanwhile, treatment with adenovirus expressing shRNA of hMOF improved OVCAR3/DDP cell xenograft sensitivity to cisplatin in mouse. Collectively, the results of the study confirm that MDM2 as a novel non-histone substrate of hMOF, participates in promoting hMOF-modulated cisplatin chemoresistance in ovarian cancer cells. hMOF/MDM2 axis might be a potential target for the treatment of chemotherapy-resistant ovarian cancer.

Signal transducer and activator of transcription 3 and cancer associated fibroblasts jointly generate chemo-resistance and affect prognosis in epithelial ovarian cancer

Objective: To investigate the mechanism of signal transducer and activator of transcription 3 (STAT3) and cancer associated fibroblasts (CAF) jointly generate chemo-resistance in epithelial-ovarian cancer and their effect on prognosis. Methods: A total of 119 patients with high-grade ovarian serous cancer who received surgery in Cancer Hospital of Chinese Academy of Medical Sciences from September 2009 to October 2017 were collected. The clinico-pathological data and follow-up data were complete. Multivariate Cox regression model was used to analyze the prognostic factors. Ovarian cancer tissue chips of patients in our hospital were prepared. EnVision two-step method immunohistochemistry was used to detect the protein expression levels of STAT3, the specific markers of CAF activation, fibroblast activating protein (FAP), and type Ⅰ collagen (COL1A1) secreted by CAF. The relationship between the expression of STAT3, FAP, COL1A1 protein and drug resistance and prognosis of ovarian cancer patients was analyzed, and the correlation between the expression of three proteins was analyzed. These results were verified through the gene expression and prognostic information of human ovarian cancer tissues collected in the GSE26712 dataset of gene expression omnibus (GEO) database. Results: (1) Multivariate Cox regression model analysis showed that chemotherapy resistance was an independent risk factor for overall survival (OS) of ovarian cancer (P<0.001). (2) The expression levels of STAT3, FAP, and COL1A1 proteins in chemotherapy resistant patients were significantly higher than those in chemotherapy sensitive patients (all P<0.05). Patients with high expression of STAT3, FAP, and COL1A1 had significantly shorter OS than those with low expression (all P<0.05). According to the human ovarian cancer GSE26712 dataset of GEO database, patients with high expression of STAT3, FAP, and COL1A1 also showed shorter OS than patients with low expression (all P<0.05), the verification results were consistent with the detection results of ovarian cancer patients in our hospital. (3) Correlation analysis showed that the protein level of STAT3 was positively correlated with FAP and COL1A1 in our hospital's ovarian cancer tissue chips (r=0.47, P<0.001; r=0.30, P=0.006), the analysis of GEO database GSE26712 dataset showed that the expression of STAT3 gene and FAP, COL1A1 gene were also significantly positively correlated (r=0.31, P<0.001; r=0.52, P<0.001). Conclusion: STAT3 and CAF could promote chemotherapy resistance of ovarian cancer and lead to poor prognosis.