Therapeutic Strategy For Ovarian Cancer Research Articles

Long Non-coding RNA FOXD2-AS1 Silencing Inhibits Malignant Behaviors of Ovarian Cancer Cells Via miR-324-3p/SOX4 Signaling Axis.

It is urgent to develop new therapeutic strategies for ovarian cancer (OC). Long-noncoding RNAs (lncRNAs) have participated in multiple biological processes including tumor recurrence and progression. This study aimed to determine the effects and potential regulatory mechanism of lncRNA FOXD2-AS1 in OC progression. Levels of lncRNA FOXD2-AS1 and miR-324-3p in OC tissues and cell lines were analyzed using quantitative real-time PCR (qRT-PCR). The direct target between FOXD2-AS1 or miR-324-3p was determined using bioinformatics tools and further verified by dual-luciferase reporter assay. Cell viability, apoptosis, migration, along invasion were assessed by MTT, flow cytometry, as well as Transwell assays, respectively. In addition, the levels of miR-324-3p, PCNA, MMP9, Bax, Bcl-2, and SOX4 in OC cells were evaluated using qRT-PCR and western blot assays. We observed that lncRNA FOXD2-AS1 was up-regulated while miR-324-3p was down-regulated in OC tissues and cell lines, especially in SKOV3 cells. Moreover, miR-324-3p was a direct target of lncRNA FOXD2-AS1. Meanwhile, SOX4 interacted with miR-324-3p and was negatively regulated by miR-324-3p in SKOV3 cells. Function assays confirmed that lncRNA FOXD2-AS1 silenced depressed cell proliferation, migration, and invasion while accelerating apoptosis. These functions of lncRNA FOXD2-AS1 were attenuated by miR-324-3p inhibition. Our research demonstrated that FOXD2-AS1 silencing restrained cell growth and metastasis of OC via regulating miR-324-3p/SOX4 axis, indicating that lncRNA FOXD2-AS1 could be a novel potential therapeutic target for OC.

Squalene monooxygenase (SQLE) protects ovarian cancer cells from ferroptosis.

Altered cholesterol metabolism has been linked to a poor prognosis in various types of cancer. Cholesterol oxidation can lead to lipid peroxidation, membrane damage, and cell death. Ferroptosis is a regulated form of cell death characterized by the accumulation of lipid peroxides, which significantly inhibits the growth of ovarian cancer cells. SQLE is the primary enzyme responsible for catalyzing cholesterol lipid synthesis and is notably expressed in ovarian cancer tissues and cells. This study aims to investigate the role of squalene monooxygenase (SQLE) in ferroptosis in ovarian cancer. The protein and mRNA expression of SQLE was assessed using qRT-PCR, Western Blot, and immunohistochemistry. The association between SQLE and ferroptosis was demonstrated through analysis of TCGA and GTEx databases, TMT protein sequencing, as well as validation by qRT-PCR, Western Blot, immunofluorescence, ROS detection, and lipid peroxide detection. Animal experiments further confirmed the relationship between SQLE and ferroptosis in ovarian cancer. The protein and mRNA expression of SQLE was found to be upregulated in both ovarian cancer tissues and cell lines. Decreased SQLE expression led to ferroptosis in ovarian cancer cells, thereby increasing their sensitivity to ferroptosis inducers. Our research demonstrates that SQLE is significantly upregulated in both ovarian cancer tissues and cells. The overexpression of SQLE in ovarian cancer may facilitate tumorigenesis by conferring resistance to ferroptosis, thus shedding light on potential novel therapeutic strategies for ovarian cancer.

Integration of hyperthermic intraperitoneal chemotherapy with cytoreductive surgery for ovarian cancer in Iraq: Navigating challenges in a resource-limited setting

In Iraq, the application of hyperthermic intraperitoneal chemotherapy combined with cytoreductive surgery is a novel therapeutic strategy for ovarian cancer with peritoneal carcinomatosis. This study at the Arby Private Hospital represents the pioneering use of this modality in a resource-limited setting. It evaluates procedural effectiveness, elucidates the systemic challenges within the healthcare framework, and identifies the imperatives for medical training enhancement. The findings illuminate the clinical viability and outline necessary strategies for broader integration of advanced therapies into the Iraqi health-care paradigm, emphasizing a pressing need for policy and infrastructural reforms to elevate oncologic care.

In Vitro and In Vivo Evaluation of the Effects of Drug 2c and Derivatives on Ovarian Cancer Cells

Background: The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting the ubiquitin-proteasome-dependent degradation of proteins. Methods: 2c phenotypic/molecular effects were studied in two OC 2D/3D culture models and in a mouse xenograft model. Furthermore, we propose an in silico model of 2c interaction with DUB-UCHL5. Finally, we have tested the effect of 2c conjugated to several linkers to generate 2c/derivatives usable for improved drug delivery. Results: 2c effectively impairs the OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs proteasome activity and triggers apoptosis, most likely by interacting with DUB-UCHL5. We also propose a mechanism for the interaction with DUB-UCHL5 via an in silico evaluation of the enzyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcription factor E2F1. Eventually, 2c activity is often retained after the conjugation with linkers. Conclusion: Our data strongly support the potential therapeutic value of 2c/derivatives in OC.

Abstract 626: EGFL6 induced HER2-HER3 signaling controls accurate centrosome deposition of activated ERK and mitotic spindle formation in ovarian cancer cells

Abstract Epidermal growth factor EGF-like domain multiple-6 (EGFL6) is highly expressed in high grade serous ovarian cancer (HGSOC) cells and ovarian tumor vasculature. EGFL6 acts on tumor cells to drive tumor cell proliferation and migration. To better understand EGFL6 signaling and develop therapeutic strategies to target EGFL6 signaling in HGSOC, we evaluated phosphorylation of putative EGFL6 receptors and their downstream signaling. We demonstrated that EGFL6 induced phosphorylation and activation of ERBB/HER family of receptors; EGFL6 treatment of ovarian cancer cells led to rapid and transient phosphorylation of EGFR while inducing prolonged activation of both HER2 and HER3, with subsequent phosphorylation of ERK. Interestingly, we found that in EGFL6 stimulated ovarian cancer cells undergoing mitosis, pERK localized to the centrosome and the contractile ring. EGFL6 neutralizing antibodies reduce ERK phosphorylation and resulted in pERK being aberrantly localized. This resulted in altered mitotic spindle alignment and an increased number of cells undergoing mitotic catastrophe. Furthermore, combination anti-EGFL6 therapy with the pan-EGFR receptor inhibitor neratinib, compared to either therapy alone, led to an increase in aberrant pERK localization and cancer cell death in vitro. Consistent with these findings, dual anti-EGFL6 and neratinib therapy significantly restricted tumor growth in vivo, resulting in increased tumor cell death and a reduction in angiogenesis. Combined our data identify an unexplored role for pERK at the centrosome and suggest that dual targeting of the EGFL6/HER signaling axis maybe an effective therapeutic strategy in ovarian cancer. Citation Format: Shoumei Bai, Navneet Gupta, Qi Jiang, Ronald J. Buckanovich. EGFL6 induced HER2-HER3 signaling controls accurate centrosome deposition of activated ERK and mitotic spindle formation in ovarian cancer cells [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 626.

TMCO1 regulates cell proliferation, metastasis and EMT signaling through CALR, promoting ovarian cancer progression and cisplatin resistance.

This study aimed to explore the involvement of Transmembrane and coiled-coil domains 1 (TMCO1) in ovarian cancer progression and its regulatory mechanisms in cisplatin resistance. Using the GEPIA database, we analyzed TMCO1 expression in ovarian cancer and normal tissues. In a cohort of 99 ovarian cancer patients, immunohistochemistry and immunofluorescence were employed to assess TMCO1 expression in tumor and adjacent tissues, correlating findings with clinical and pathological characteristics. TMCO1 overexpression and knockout cell models were constructed, and their impact on non-cisplatin-resistant (SK-OV-3) and cisplatin-resistant (SK-OV-3-CDDP) ovarian cancer cells was investigated through cloning, wound healing, Fluo 4, and Transwell experiments. Knocking down CALR and VDAC1 was performed to examine their effects on TMCO1, cell proliferation, and malignant markers. Subcutaneous tumor models in nude mice elucidated the in vivo role of TMCO1 in tumor growth. Expression levels of CALR, VDAC1, angiogenesis indicators (CD34), and epithelial-mesenchymal transition (EMT) markers were evaluated. TMCO1 expression in ovarian cancer tissue significantly differed from normal tissue, correlating with survival rates. TMCO1 overexpression was associated with lymph node metastases, late FIGO stage, and larger tumors. TMCO1 promoted proliferation, calcium ion elevation, cytoskeletal remodeling, and metastasis in SK-OV-3 and SK-OV-3-CDDP cells, upregulating VDAC1, CALR, Vimentin, N-cadherin, β-catenin, and downregulating E-cadherin. Silencing TMCO1 inhibited cell growth, proliferation, and angiogenesis in vivo, suppressing the expression of CALR, VDAC1, Vimentin, N-cadherin, and β-catenin. Overall, this study highlighted TMCO1 as a crucial regulator in ovarian cancer progression, influencing VDAC1 through CALR and impacting diverse cellular processes, offering potential as a targeted therapeutic strategy for ovarian cancer.

Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer.

Ovarian cancer is one of the tumors with the highest fatality rate among gynecological tumors. The current 5-year survival rate of ovarian cancer is <35%. Therefore, more novel alternative strategies and drugs are needed to treat ovarian cancer. The transcription factor B-cell lymphoma 6 (BCL6) is critically associated with poor prognosis and cisplatin resistance in ovarian cancer treatment. Therefore, BCL6 may be an attractive therapeutic target for ovarian cancer. However, the role of targeting BCL6 in ovarian cancer remains elusive. Here, we developed a novel BCL6 small molecule inhibitor, WK369, which exhibits excellent anti-ovarian cancer bioactivity, induces cell cycle arrest and causes apoptosis. WK369 effectively inhibits the growth and metastasis of ovarian cancer without obvious toxicity in vitro and in vivo. meanwhile, WK369 can prolong the survival of ovarian cancer-bearing mice. It is worth noting that WK369 also has significant anti-tumor effects on cisplatin-resistant ovarian cancer cell lines. Mechanistic studies have shown that WK369 can directly bind to the BCL6-BTB domain and block the interaction between BCL6 and SMRT, leading to the reactivation of p53, ATR and CDKN1A. BCL6-AKT, BCL6-MEK/ERK crosstalk is suppressed. As a first attempt, our study demonstrates that targeting BCL6 may be an effective approach to treat ovarian cancer and that WK369 has the potential to be used as a candidate therapeutic agent for ovarian cancer.

Glycyrrhizic acid enhances the anticancer activity of cisplatin in the human ovarian cancer cell line

This study aimed to investigate the effects of glycyrrhizic acid (GL) on the anticancer activity of cisplatin in A2780 ovarian cancer cells. Cultured A2780 cells were treated with different concentrations of GL and cisplatin individually and in combination. The MTT assay, flow cytometry, wound-healing, and clonogenic assay, were used to determine cell viability, apoptosis, migration, and colony formation, respectively. The effects on superoxide dismutase (SOD) activity were also evaluated. QPCR was used to study the effects of individual and combined treatments with GL and cisplatin on the expression levels of migration genes (MMP2 and MMP9), and some apoptosis pathway genes (caspase-3, −8, −9, and BCL2). A synergistic effect was observed between GL and cisplatin (CI < 1). Combination therapy was significantly more effective in reducing cell viability, suppressing migration and colony formation, inducing apoptosis, and altering gene expression compared to single therapies. GL significantly increased SOD activity. The relative expression of caspase −3, −8, and − 9 increased significantly, and the expression levels of MMP2 and MMP9 decreased significantly in the treated cells. Our results indicate that GL enhances the anticancer activity of cisplatin in the A2780 cell line. Therefore, the combination of GL and cisplatin can be proposed as a promising therapeutic strategy for ovarian cancer.

ANGPTL3 affects the metastatic potential and the susceptibility of ovarian cancer cells to natural killer cell-mediated cytotoxicity

High metastatic potential and resistance to immunotherapy lead to poor survival in patients with ovarian cancer. Angiopoietin-like protein 3 is aberrantly expressed and exerts diverse roles in the progression of several cancers. However, its function in ovarian cancer is unknown. Here, decreased expression of angiopoietin-like protein 3 was observed in ovarian cancer tissues and cells. Moreover, patients with high expression of angiopoietin-like protein 3 had longer overall survival and progression-free survival, indicating a good prognosis for patients. Furthermore, angiopoietin-like protein 3 overexpression inhibited ovarian cancer cell proliferation. Concomitantly, high invasion and the occurrence of epithelial-to-mesenchymal transition of cancer cells were restrained after angiopoietin-like protein 3 elevation. Up-regulation of angiopoietin-like protein 3 expression further increased interleukin 2-treated natural killer cell activation by increasing CD69 expression and production of interferon gamma and tumor necrosis factor-alpha when natural killer cells were co-cultured with ovarian cancer cells. Importantly, angiopoietin-like protein 3 overexpression enhanced natural killer cell-evoked cytotoxicity and apoptosis of cancer cells, indicating the pro-tumor killing ability of angiopoietin-like protein 3 for natural killer cells. Mechanistically, angiopoietin-like protein 3 elevation inhibited activation of the Janus Kinase/Signal transducer and activator of transcription 3 signaling in ovarian cancer cells by inhibiting protein expression of phospho-Janus Kinase 2, phospho-Signal transducer and activator of transcription 3, downstream matrix metallopeptidase 2 and programmed cell death 1. Moreover, blocking the Janus Kinase/Signal transducer and activator of transcription 3 pathway via their inhibitor Stattic restrained ovarian cancer cell proliferation, invasion, epithelial-to-mesenchymal transition, and promoted natural killer cell killing to ovarian cancer cells. Thus, these findings reveal that angiopoietin-like protein 3 may act as an anti-oncogenic regulator to inhibit the metastatic potential and enhance the susceptibility of ovarian cancer cells to natural killer cell-mediated killing. Consequently, angiopoietin-like protein 3 may regulate metastatic potential and immune escape from natural killer cells, indicating a promising therapeutic strategy for ovarian cancer.

Metal-organic framework-encapsulated dihydroartemisinin nanoparticles induces apoptotic cell death in ovarian cancer by blocking ROMO1-mediated ROS production

Dihydroartemisinin (DHA), a natural product derived from the herbal medicine Artemisia annua, is recently used as a novel anti-cancer agent. However, some intrinsic disadvantages limit its potential for clinical management of cancer patients, such as poor water solubility and low bioavailability. Nowadays, the nanoscale drug delivery system emerges as a hopeful platform for improve the anti-cancer treatment. Accordingly, a metal-organic framework (MOF) based on zeolitic imidazolate framework-8 was designed and synthesized to carry DHA in the core (ZIF-DHA). Contrast with free DHA, these prepared ZIF-DHA nanoparticles (NPs) displayed preferable anti-tumor therapeutic activity in several ovarian cancer cells accompanied with suppressed production of cellular reactive oxygen species (ROS) and induced apoptotic cell death. 4D-FastDIA-based mass spectrometry technology indicated that down-regulated reactive oxygen species modulator 1 (ROMO1) might be regarded as potential therapeutic targets for ZIF-DHA NPs. Overexpression of ROMO1 in ovarian cancer cells significantly reversed the cellular ROS-generation induced by ZIF-DHA, as well as the pro-apoptosis effects. Taken together, our study elucidated and highlighted the potential of zeolitic imidazolate framework-8-based MOF to improve the activity of DHA to treat ovarian cancer. Our findings suggested that these prepared ZIF-DHA NPs could be an attractive therapeutic strategy for ovarian cancer.

OncoTherad immunotherapy plus platelet rich plasma as potential therapeutic strategy for ovarian cancer: The role of toll-like receptors 2 and 4 signaling pathways.

e17602 Background: Ovarian cancer (OC) has the most devastating death rate of gynecological cancers with only 44% of women surviving 5 years after diagnosis. Toll-like receptors (TLRs) signaling can play an important role in the OC treatment. TLR activation in immune cells can help activate an effective antitumor response. In this scenario, a new perspective is represented by combined OncoTherad (MRB-CFI-1) immunotherapy and Platelet Rich Plasma (PRP). OncoTherad (MRB-CFI-1) leads to the distinct stimulation of the innate immune system mediated by TLR2 and TLR4, resulting in an increased activation of the IFN signaling pathway. Also, PRP acts on immune activation and exerts antitumor effects. This study characterized the histopathological and molecular effects of the OncoTherad associated with PRP in the treatment of OC chemically induced in rats and described the possible mechanisms of action of this association involving the TLRs 2 and 4 signaling pathways. Methods: Fischer 344 female rats were divided into 5 groups (n = 7 animals per group): Control (Sham surgery) group; Cancer (7,12 dimethylbenzoanthracene – DMBA injection in the ovarian bursa, 1.25 mg/kg) group; OncoTherad (20mg/kg) group; PRP (328.103 – 549.103 platelets/mm3) group and; OncoTherad+PRP (same doses of the isolated treatments) group. Intraperitoneal doses were administered twice a week for 4 weeks. Immunohistochemistry was analyzed as total immunoreactivity and intensity of immunoreaction. Results: Our results showed serous type ovarian carcinoma, follicular atresia, absence of corpora lutea and hyperplasia of the germinal epithelium and tunica albuginea in the Cancer group. The histopathological changes in the PRP group were similar as Cancer group. In contrast, the animals treated with OncoTherad singly or in combination with PRP showed decrease of ovarian neoplastic lesions and histopathological recovery. TLR4 and IL-6 immunoreactivities were significantly lower (p &lt; 0.05) in the Cancer group. PRP treatment reduced (p &lt; 0.05) TLR2. In the Oncotherad+PRP group, the immunoreactivities of TLR4, MyD88, IRF-3 and TNF-α were lower. OncoTherad treatment alone led to stimulation of the innate immune system mediated by TLR2 and TLR4, resulting in an increased activation of the MyD88 signaling pathway (intensified IL-6 and TNF-α immunoreactivities). Conclusions: OncoTherad immunotherapy was able to reduce ovarian lesions and stimulated the TLR2 and 4 signaling pathways in the OC microenvironment, leading to antitumor effects by activating the production of inflammatory cytokines. Thus, OncoTherad immunotherapy could be considered an important therapeutic strategy for OC.

C-MYC-Driven Polyamine Metabolism in Ovarian Cancer: From Pathogenesis to Early Detection and Therapy.

c-MYC and its paralogues MYCN and MYCL are among the most frequently amplified and/or overexpressed oncoproteins in ovarian cancer. c-MYC plays a key role in promoting ovarian cancer initiation and progression. The polyamine pathway is a bona fide target of c-MYC signaling, and polyamine metabolism is strongly intertwined with ovarian malignancy. Targeting of the polyamine pathway via small molecule inhibitors has garnered considerable attention as a therapeutic strategy for ovarian cancer. Herein, we discuss the involvement of c-MYC signaling and that of its paralogues in promoting ovarian cancer tumorigenesis. We highlight the potential of targeting c-MYC-driven polyamine metabolism for the treatment of ovarian cancers and the utility of polyamine signatures in biofluids for early detection applications.

MicroRNA-592 Inhibits the Growth of Ovarian Cancer Cells by Targeting ERBB3.

Objectives: Ovarian cancer is the most lethal gynecologic malignancy, and targeted therapy for different pathological types and molecular phenotypes is urgent to be studied. Studies have shown that MicroRNA-592 (miR-592) plays an important negative regulatory role in the occurrence of gastrointestinal malignancies, breast cancer, non-small cell lung cancer, and glioma, but the expression of miR-592 in ovarian cancer and the mechanism of action are still unclear. Methods: The expressions of miR-592 were examined by RT-PCR and Western Blot. Cell viability and migratory capacity were detected by CCK-8 and transwell assay. TargetScan (http://www.targetscan.org) was analyzed to predict potential targets of miR-592. Then Dual-luciferase reporter gene assay was performed to verify the targeting relationship between miR-592 and ERBB3. A mouse xenograft model was applied to confirm the effect of miR-592. Results: In our study, we found that the expression of miR-592 is reduced in epithelial ovarian cancer tissues. The exogenous expression of miR-592 inhibits the proliferation, migration, and invasion in epithelial ovarian cancer tumor cells. Furthermore, the exogenous expression of miR-592 inhibits tumor growth in the nude mouse xenograft model. Therefore, miR-592 may play a role of tumor suppressor miRNA in the occurrence and development of ovarian cancer. Further experiments demonstrated that tumor-related ERBB3 is a target gene mediated by miRNA-592. The dual-luciferase reporter system was used to identify miRNA-592 target genes; qPCR and Western Blot were used to detect the expression of ERBB3. Mechanical experiments confirmed that miRNA-592 negatively regulated ERBB3.Conclusion: Together, these findings identify a heretofore unrecognized link between miR-592 and ERBB3 and suggest that targeting on miR-592 warrants attention as a novel and potential therapeutic strategy for ovarian cancer.

Anlotinib Suppressed Ovarian Cancer Progression via Inducing G2/M Phase Arrest and Apoptosis

Ovarian cancer remains the most common gynecologic malignancy, because of its chemotherapy resistance and relapse. Anlotinib, a new oral multi-targeted tyrosine kinase inhibitor, has shown encouraging antitumor activity in several preclinical and clinical trials, while its effect on ovarian cancer has not been reported. In this study, we investigated the antitumor activity and underlying mechanism of anlotinib in ovarian cancer. Cell viability was analyzed by Cell Counting Kit-8 assay. Migration was measured by wound-healing assay. The cell cycle distribution and cell apoptosis rate were detected by flow cytometry. In vivo antitumor effect was analyzed in mouse ovarian carcinoma peritoneal metastasis model. We found that anlotinib inhibited the proliferation of ovarian cancer cells in a dose- and time- dependent manner by inducing G2/M phase arrest and apoptosis. Moreover, anlotinib upregulated the the phosphorylation of Histone H3, and expression of p21 protein in vitro. In addition, anlotinib inhibited the migration of ovarian cancer cells in vitro. Furthermore, anlotinib inhibited tumor growth by inhibiting cell proliferation and suppressing ovarian cancer angiogenesis in vivo. This study demonstrated the extraordinary anti-ovarian cancer effect of anlotinib, which may provide a promising therapeutic strategy for ovarian cancer.

Natural melanin-based nanoparticles with photothermal/photodynamic activities induce ovarian cancer cell death

To investigate the physicochemical characteristics of natural melanin-like nanoparticles (PDA NPs) and their synergistic anti-tumor efficacy with photothermal and photodynamic (PTT/PDT) therapy. The chemically synthesized PDA NPs were characterized using transmission electron microscope (TEM), dynamic light scattering (DLS) and Zeta potential analysis, and their photothermal and photodynamic properties were assessed with near-infrared excitation light (NIR). The antitumor efficacy of free PDA or PDA combined with NIR irradiation (0.7 and 1.0 W/cm2) was evaluated in ovarian cancer cells using flow cytometry, Cell Counting Kit-8 (CCK-8), and Transwell assay and in a mouse model bearing subcutaneous ovarian cancer xenograft. The synthesized PDA NPs showed a spherical morphology with diameters around 100 nm and a zeta potential of -20 mV. Upon NIR irradiation at 0.7 and 1.0 W/cm2, the particles underwent temperature changes (ΔT) of about 15 and 30 ℃, respectively, and produced a large amount of singlet oxygen, demonstrating their excellent PTT/PDT properties. In ovarian cancer cells, treatment with PDA NPs alone did not induce obvious changes in reactive oxygen species (ROS) production or mitochondrial membrane potential (MTP), but when combined with NIR irradiation, these particles caused a significant increase of ROS and a reduction of MTP (P < 0.001), and such changes were more prominent with high power NIR (P < 0.01). PDA NPs alone showed no obvious cytotoxicity, but the combination of PDA with NIR irradiation produced potent killing effect on ovarian cancer cells (P < 0.001), and the effect was much stronger with a high power irradiation (P < 0.001). While PDA alone showed no inhibitory effect on tumor cell metastasis, the combined treatment with PDA and NIR irradiation, especially at a high power, significantly suppressed invasion and migration of ovarian cancer cells (P < 0.001). In the tumor-bearing mouse model, the combined treatment, but not PDA alone, produced a significant inhibitory effect on tumor growth (P < 0.001). PDA NPs combined with NIR has a strong anti-tumor effect, suggesting a potential new therapeutic strategy for ovarian cancer.

LncRNA KCNQ1OT1 promotes the metastasis of ovarian cancer by increasing the methylation of EIF2B5 promoter

BackgroundLong non-coding RNAs (lncRNAs) have emerged as regulators of human malignancies, including ovarian cancer (OC). LncRNA KCNQ1OT1 could promote OC progression, and EIF2B5 was associated with development of several tumors. This project was aimed to explore the role of lncRNA KCNQ1OT1 in OC development, as well as the involving action mechanism.MethodsReverse transcription quantitative polymerase chain reaction (RT-qPCR) or Western blotting was employed to determine the expression levels of KCNQ1OT1 and EIF2B5. OC cell proliferation was evaluated by MTT and colony formation assays, and wound healing and Transwell assays were implemented to monitor cell migration and invasion, respectively. The methylation status of EIF2B5 promoter was examined by MS-PCR, to clarify whether the expression of EIF2B5 was decreased. The binding activity of KCNQ1OT1 to methyltransferases DNMT1, DNMT3A and DNMT3B was determined by dual luciferase reporter assay or RIP assay, to explore the potential of KCNQ1OT1 alters the expression of its downstream gene. ChIP assay was carried out to verify the combination between EIF2B5 promoter and above three methyltransferases.ResultsExpression of lncRNA KCNQ1OT1 was increased in OC tissues and cells. EIF2B5 expression was downregulated in OC, which was inversely correlated with KCNQ1OT1. Knockdown of KCNQ1OT1 inhibited OC cell proliferation and metastasis. KCNQ1OT1 could downregulate EIF2B5 expression by recruiting DNA methyltransferases into EIF2B5 promoter. Furthermore, interference of EIF2B5 expression rescued KCNQ1OT1 depletion-induced inhibitory impact on OC cell proliferation and metastasis.ConclusionOur findings evidenced that lncRNA KCNQ1OT1 aggravated ovarian cancer metastasis by decreasing EIF2B5 expression level, and provided a novel therapeutic strategy for OC.

Targeting human caseinolytic protease P (ClpP) as a novel therapeutic strategy in ovarian cancer

AbstractOvarian cancer (OC) is currently one of the most life‐threatening types of gynecological malignancy with limited treatment options and poor clinical outcomes. Human caseinolytic protease P (HsClpP) is located in the mitochondria and plays an important role in several tumors. Moreover, HsClpP is overexpressed in OC and several other tumor cells. Thus, HsClpP modulation is regarded as a potential approach for OC treatment. In this study, we identified and validated a novel boron peptide Compound 43‐8F as a potent HsClpP inhibitor. Upon 43‐8F treatment, mitochondrial damage was observed to be closely correlated with upregulated intracellular reactive oxygen species production, decreasement of membrane potential, and ATP content suppression. Meanwhile, the expression level of SDHB and the ATF4 was increased after 43‐8F treatment, suggesting that 43‐8F treatment induces mitochondrial respiratory disorders and activates the integrated stress response pathway to inhibit tumor cell growth. Further, 43‐8F exhibited a good therapeutic and safety profile in OC xenograft model in nude mice. Together, these results suggest that 43‐8F exerts an anti‐ovarian cancer effect by inhibiting HsClpP pathway.

Non-Coding RNAs Delivery by Small Extracellular Vesicles and Their Applications in Ovarian Cancer.

Ovarian cancer (OC) is the most fatal gynecological malignancy because of its early asymptomatic nature and acquired resistance to chemotherapy. Small extracellular vesicles (sEVs) are a heterogeneous group of biological vesicles with a diameter <200 nm released by cells under physiological or pathological conditions. sEVs-derived non-coding RNAs (ncRNAs) are the essential effectors in the biological environment. sEVs-ncRNAs have critical roles in tumor progression via regulating mRNA expression of target cells to affect cell signaling. In addition, the status of parental cells can be disclosed via analyzing the composition of sEVs-ncRNAs, and their “cargoes” with specific changes can be used as key biomarkers for the diagnosis and prognosis of OC. Accumulating evidence has demonstrated that sEVs-ncRNAs are involved in multiple key processes that mediate the development of metastasis and chemotherapeutic resistance in OC: epithelial–mesenchymal transition; tumorigenicity of mesenchymal stem cells; immune evasion; angiogenesis. The nanomedicine delivery system based on engineering sEVs is expected to be a novel therapeutic strategy for OC. Insights into the biological roles of sEVs-ncRNAs in the invasion, metastasis, immune regulation, and chemoresistance of OC will contribute to discovery of novel biomarkers and molecular targets for early detection and innovative therapy. In this review, we highlight recent advances and applications of sEVs-ncRNAs in OC diagnosis and treatment. We also outline current challenges and knowledge gaps.

Wnt/β-Catenin Inhibition by CWP232291 as a Novel Therapeutic Strategy in Ovarian Cancer.

The poor prognosis of ovarian cancer patients mainly results from a lack of early diagnosis approaches and a high rate of relapse. Only a very modest improvement has been made in ovarian cancer patient survival with traditional treatments. More targeted therapies precisely matching each patient are strongly needed. The aberrant activation of Wnt/β-catenin signaling pathway plays a fundamental role in cancer development and progression in various types of cancer including ovarian cancer. Recent insight into this pathway has revealed the potential of targeting Wnt/β-catenin in ovarian cancer treatment. This study aims to investigate the effect of CWP232291, a small molecular Wnt/β-catenin inhibitor on ovarian cancer progression. Various in vitro, in vivo and ex vivo models are established for CWP232291 testing. Results show that CWP232291 could significantly attenuate ovarian cancer growth through inhibition of β-catenin. Noticeably, CWP232291 could also s suppress the growth of cisplatin-resistant cell lines and ovarian cancer patient-derived organoids. Overall, this study has firstly demonstrated the anti-tumor effect of CWP232291 in ovarian cancer and proposed Wnt/β-catenin pathway inhibition as a novel therapeutic strategy against ovarian cancer.

Therapeutic Strategies for Ovarian Cancer in Point of HGF/c-MET Targeting.

Ovarian cancer is the fifth leading cause of cancer deaths in women and is regarded as one of the most difficult cancers to treat. Currently, studies are being conducted to develop therapeutic agents for effective treatment of ovarian cancer. In this review, we explain the properties of the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) and how the signaling pathway of HGF/c-MET is activated in different cancers and involved in tumorigenesis and metastasis of ovarian cancer. We present the findings of clinical studies using small chemicals or antibodies targeting HGF/c-MET signaling in various cancer types, particularly in ovarian cancer. We also discuss that HGF/c-MET-targeted therapy, when combined with chemo drugs, could be an effective strategy for ovarian cancer therapeutics.