Ovarian Cancer Growth Research Articles

The chemokine CX3CL1 promotes intraperitoneal tumour growth despite enhanced T-cell recruitment in ovarian cancer.

T-cell recruiting chemokines are required for a successful immune intervention in ovarian cancer, and also for the efficacy of modern anticancer agents such as PARP inhibitors. The chemokine CX3CL1 recruits tumour-suppressive T-cells into solid tumours, but also mediates cell-cell adhesions, e.g. of tumour cells, through its membrane-bound form. So far, its role in ovarian cancer has only been rudimentarily addressed. We show that high CX3CL1 expression significantly correlates with worsened survival in human high-grade serous ovarian cancer (n=219). In preclinical ovarian cancer, CX3CL1 plays a dual role, as it enhances the adaptive anti-tumour response, but overall still promotes tumour growth, the latter as a feature of the intraperitoneal environment. Moreover, PARP inhibitors are able to increase CX3CL1 release from human ovarian cancer cells. Collectively, our study shows that CX3CL1 is a driver of intraperitoneal tumour growth in ovarian cancer, a feature that may compromise the anticancer effect of CX3CL1-inducing PARP inhibitors.

Processed Products of Aconitum soongaricum Stapf. Inhibit the Growth of Ovarian Cancer Cells In vivo via Regulating the PI3K/AKT Signal Pathway.

The alkaloids of songorine, aconitine, and benzoylaconitine, as the processed products of Aconitum soongaricum Stapf., can significantly inhibit the migration and invasion of ovarian cancer cells in vitro. Herein, we studied the in vivo role and mechanism of these natural products in processed A. soongaricum Stapf. A xenograft tumor model was constructed. Tumor volumes and weights were calculated. HE staining assessed the histopathological changes of tumors. Inflammatory factors were detected using ELISA. Gene and protein expressions of E-cadherin, N-cadherin, PIK3CA, and AKT1 proteins were measured using RT-qPCR and immunohistochemistry. Protein expressions of E-cadherin, N-cadherin, PIK3CA, AKT1, p-PIK3CA, and p- AKT1 proteins were detected using western blot analysis. Songorine, aconitine, and benzoylaconine significantly inhibited the growth of tumors as evidenced by decreased tumor volume and weight. The extent and scope of tumor cell necrosis were less in the songorine group compared to the vehicle group. Songorine, aconitine, and benzoylaconine significantly reduced IL-6, IL-1β, and TNF-α levels. Furthermore, songorine, aconitine, and benzoylecgonine induced down-regulation of N-cadherin and AKT1 mRNA in comparison to the vehicle group. Meanwhile, songorine, aconitine, and benzoylaconine also significantly reduced N-cadherin, p-PIK3CA, and p-AKT1 proteins, while upregulating E-cadherin protein expression in comparison to the vehicle group. These effects were further enhanced when combined with the PI3K inhibitor LY294002. Songorine, aconitine, and benzoylaconine may inhibit ovarian cancer growth in vivo by blocking the PI3K/AKT signaling pathway. Our findings may provide evidence for the clinical application of the processed products of Aconitum soongaricum Stapf. in ovarian cancer treatment.

A targetable OSGIN1 − AMPK − SLC2A3 axis controls the vulnerability of ovarian cancer to ferroptosis

Despite advances in various chemotherapy regimens, current therapeutic options are limited for ovarian cancer patients. Oxidative stress-induced growth inhibitor 1 (OSGIN1), which is a tumor suppressor gene known to regulate the cellular stress response and apoptosis, is associated with ovarian cancer development. However, the underlying mechanisms involved in ferroptosis regulation have not been elucidated. Thus, this study aimed to investigate the effect and underlying regulatory mechanism of the OSGIN1 gene on ovarian cancer cells. Our results demonstrated that loss of the OSGIN1 gene promoted ovarian cancer growth and conferred resistance to drug-induced ferroptosis. Mechanistically, the loss of OSGIN1 activates AMPK signaling through ATM, leading to the upregulation of SLC2A3, which protects cells from ferroptosis and renders them insensitive to ferroptosis inducers. Notably, an SLC2A3-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on ovarian cancer patient-derived xenograft tumors. Overall, anti-SLC2A3 therapy is a promising method to improve ovarian cancer treatment by targeting ferroptosis.

Melittin suppresses ovarian cancer growth by regulating SREBP1-mediated lipid metabolism.

Melittin, a major peptide component of bee venom, has demonstrated promising anti-cancer activity across various preclinical cell models, making it a potential candidate for cancer therapy. However, its molecular mechanisms, particularly in ovarian cancer, remain largely unexplored. Ovarian cancer is a life-threatening gynecological malignancy with poor clinical outcomes and limited treatment options. This study evaluated the efficacy of melittin in suppressing ovarian cancer and elucidated its underlying molecular mechanisms. A subcutaneous xenograft tumor model was established using ID8 cells in C57BL/6J mice. RNA sequencing revealed that melittin's anticancer effects were associated with the downregulation of lipid metabolism, particularly fatty acid synthesis. The impact of melittin on de novo fatty acid synthesis was assessed by measuring free fatty acid (FFA), triglyceride (TG), and total cholesterol (TC) levels in ovarian cancer cells. Lipogenic gene expression and sterol regulatory element-binding protein 1 (SREBP1) were analyzed by Western blot and quantitative real-time polymerase chain reaction. The regulation of FASN transcription by SREBP1 was explored using a dual-luciferase reporter assay. Plasmid DNA transfection and the SREBP1 inhibitor Fatostatin were employed to identify the signaling pathway mediating melittin's anticancer effects. Our results confirmed that melittin significantly reduced de novo fatty acid synthesis, as evidenced by lower FFA, TG, and lipid droplet levels. Additionally, melittin inhibited the nuclear translocation of SREBP1 and specifically reduced SREBP1-mediated FASN transcription, demonstrating effects similar to those of Fatostatin. The motif (-424/-415) within the FASN promoter is a potential SREBP-1 binding site. SREBP1 overexpression through plasmid DNA transfection significantly counteracted melittin's downregulation of FASN promoter activity and counteracted its inhibitory effects on de novo fatty acid synthesis, cell proliferation, and colony formation. Our findings suggested that melittin acts as a novel modulator of the SREBP1/FASN pathway, reducing lipogenesis and inhibiting ovarian cancer growth. This study was the first to demonstrate melittin's ability to target the SREBP1/FASN axis in ovarian cancer, identifying SREBP1 as a novel therapeutic target. These results highlighted melittin as a potential therapeutic agent for ovarian cancer by attenuating SREBP1-mediated lipid metabolism and suggested novel treatment strategies for targeting ovarian cancer.

Tanshinone I reprograms glycolysis metabolism to regulate histone H3 lysine 18 lactylation (H3K18la) and inhibits cancer cell growth in ovarian cancer.

Salvia miltiorrhiza, the anticancer properties of these components are multifaceted, encompassing the inhibition of tumor growth, prevention of the metastatic spread of cancer cells, enhancement of the sensitivity of cancer cells to chemotherapy and radiation therapy, and the suppression of angiogenesis, which is crucial for tumor growth and survival. In the context of our recent study, we have discovered that tanshinone I, one of the active components of Salvia miltiorrhiza, possesses the ability to inhibit the proliferation of ovarian cancer cells, both in laboratory settings and within living organisms. To further understand the molecular mechanisms behind this effect, we conducted a comprehensive transcriptomic analysis. Our findings indicated that tanshinone I exerts its inhibitory action by downregulating the expression of genes associated with glycolysis. Specifically, tanshinone I decreased the expression of glycolysis-related genes such as HK2 (hexokinase 2), PFK (phosphofructokinase), ENO2 (enolase 2), and LDHA (lactate dehydrogenase A). Inhibiting lactate production by tanshinone I application reduced the level of histone H3 lysine 18 lactylation (H3K18la), which reduced the expression of tumor-associated genes, such as TTK, PDGFRβ, YTHDF2 and RUBCNL. In addition, tanshinone I alleviated the immunosuppressive tumor microenvironment. In summary, tanshinone I blocks glycolysis to regulate histone H3 lysine 18 lactylation (H3K18la), which inhibits ovarian cancer cell growth, revealing the anticancer mechanism of tanshinone I.

Artesunate disrupts ribosome RNA biogenesis and inhibits ovarian cancer growth by targeting FANCA.

The dysregulation of ribosome biogenesis has been extensively identified in various cancers, making it emerge as a hallmark of malignant cells. This highlights the potential of targeting ribosome biogenesis as an effective approach for treating cancer patients. Although chemotherapy drugs including doxorubicin and cisplatin often target ribosome biogenesis to induce DNA damage or inhibit tumor cell proliferation, they are associated with significant side effects. This study aims to reveal the novel role of artesunate (ART), a well-known antimalarial drug, in suppressing ribosome RNA biogenesis in ovarian cancer. In this study, the inhibitory effects of ART on ovarian cancer were studied both in vitro and in vivo. The effects of ART on ribosome RNA biogenesis were detected by 5-ethynyl uridine staining, RT-qPCR, and western blotting. Drug affinity responsive target stability, mass spectrometry, molecular docking and western blotting were combined to identify ART molecular targets. Ovarian cancer cells treated with ART exhibited significant reduction in nascent rRNA synthesis, accompanied by a remarkable down-regulation of pre-rRNA and mature rRNA expression. The inhibitory effect of ART on ribosome biogenesis subsequently impaired cell proliferation, cell migration and invasion, and induced apoptosis. In eukaryotes, ribosome RNA synthesis primarily occurs in the nucleus, involving processes such as rDNA transcription, pre-rRNA splicing and the assembly of ribosome precursors with ribosomal proteins, other closely-related proteins and small nucleolar RNAs. We observed that ART inhibited the nuclear translocation of FANCA through binding to FANCA protein, consequently leading to the inhibition of ribosome RNA synthesis. Moreover, knockdown of FANCA in ovarian tumor cells resulted in reduced rRNA transcription, suppressed cell proliferation and migration, and induced apoptosis which might be mediated through the inhibition of mTOR/RPS6 activity. In vivo studies using xenograft tumors in nude mice demonstrated that ART repressed the growth of established ovarian cancer tumors. Additionally, ART treatment significantly altered FANCA protein level in these tumors, especially suppressed its nuclear localization. These findings establish ART as a potent inhibitor of ribosome biogenesis, presenting a promising therapeutic avenue for ovarian tumors with high FANCA expression or for cancer patients exhibiting abnormal activation of the mTOR-RPS6 pathway.

HDC downregulation induced by chronic stress promotes ovarian cancer progression via the IL-6/STAT3/S100A9 pathway

ObjectiveThis study aimed to investigate the underlying mechanism of chronic stress promoting ovarian cancer growth comorbid with depression and evaluate the potential role of histamine (HIS) in treating this comorbidity.MethodsChronic unpredictable mild stress (CUMS) was used to establish a comorbid mouse model of ovarian cancer and depression. The behavioral phenotypes were assessed using the sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and open field test (OFT). Ovarian cancer growth was monitored by tracking the tumor volume and weight. Histidine decarboxylase (HDC) expression in the tumor tissue was analyzed using Western blot and qRT-PCR techniques. The serum levels of inflammatory factors (IL-6 and IL-17A), stress hormones (norepinephrine, NE and cortisol, and COR), histamine, and 5-hydroxytryptamine (5-HT) were detected by enzyme-linked immunosorbent assay (ELISA). In vitro experiments were conducted to explore the direct impacts of stress hormones on A2780 and ES-2 ovarian cancer cell lines, as well as the modulation of these effects by histamine. HDC knockdown and overexpression approaches were used to study its regulatory role in the IL-6/STAT3/S100A9 signaling pathway.ResultsChronic stress not only induced depressive behaviors but also accelerated ovarian cancer growth in mice by downregulating HDC expression in tumors, whereas exogenous HIS treatment alleviated depressive symptoms, suppressed cancer growth, and countered the decreased levels of HIS and increased levels of IL-6, IL-17A, NE, COR, and 5-HT induced by CUMS. Furthermore, HIS positively modulated the immune response by increasing the populations of CD3+T and CD8+ T cells and reducing IL-17A secretion. In vitro experiments revealed that stress hormones downregulated HDC expression, consequently promoting cancer cell proliferation, migration, and invasion via the IL-6/STAT3/S100A9 pathway. Knockdown of HDC activated this pathway, whereas HDC overexpression inhibited its activation.ConclusionChronic stress leads to the downregulation of HDC expression, thereby facilitating the progression of ovarian cancer through the IL-6/STAT3/S100A9 pathway. HIS might serve as a potential molecule for treating the comorbidities of ovarian cancer and depression.

Abstract PR010: TRPV1+ sensory innervation as a novel driver of ovarian cancer progression

Abstract Introduction: A primary challenge currently faced in ovarian cancer (OVCA) treatment is that patient prognoses remain poor despite current therapeutic interventions. Overall survival for OVCA patients with advanced disease is <30%, and most patients recur within 5 years. As such, there is a critical need for new therapies that can overcome OVCA chemoresistance and produce meaningful increases in patient survival. Recent efforts that have targeted the tumor microenvironment (TME), such as immune checkpoint inhibitors, have been successful in some cancers but have limited therapeutic benefit when used to treat OVCA. Thus, new TME targeting therapies must be developed to effectively treat OVCA patients. A novel TME component ripe for therapeutic targeting are the nerve fibers that infiltrate tumors. Recent studies in several cancers have shown that tumor innervation can promote tumor growth/metastasis. However, in ovarian cancer the role of innervation in promoting cancer progression remains a gap in knowledge. Here we show that Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1)+ sensory innervation plays a significant role in driving ovarian cancer progression. Methods: We performed IHC staining to determine the extent of TRPV1+ nerve infiltration in OVCA vs normal reproductive tissue in patients. We examined the ability of OVCA cells to promote tumor innervation using a neurite outgrowth assay. We utilized both syngeneic and patient derived xenograft (PDX) mouse models of ovarian cancer metastasis, where mouse or human OVCA cells were injected intraperitoneally, to explore the functional role of TRPV1+ sensory nerves in OVCA. TRPV1+ sensory nerves were ablated genetically using TRPV1 driven expression of diphtheria toxin alpha (DTA) or chemically using resiniferatoxin. TRPV1+ sensory nerves were activated pharmacologically using capsaicin. Results: Analysis of patient samples showed that TRPV1+ sensory innervation is much higher in ovarian tumors vs benign reproductive tissue. We found that conditioned media from OVCA cells was able to promote neurite outgrowth of dissociated mouse sensory neurons. Ablation of TRPV1+ sensory nerve fibers in vivo caused reduced tumor burden and prolonged survival in our syngeneic and PDX OVCA mouse models. Stimulation of TRPV1+ sensory nerves with capsaicin accelerated OVCA growth and decreased survival in tumor bearing mice. Conclusions: Our results establish TRPV1+ sensory innervation as a novel driver of OVCA growth/metastasis and a potential therapeutic target for OVCA treatment. Significance to tumor microenvironment field: Our data add to a growing body of evidence that sensory nerves are pro-tumorigenic in multiple cancer types and could be therapeutically targeted for cancer treatment. Citation Format: Matthew Knarr, Katherine Cummins, Dusan Racordon, Hunter Reavis, Timothy Lippert, Ryan Hausler, Priyanka Rawat, Jamie Moon, Dave S.B. Hoon, Roger Greenberg, Paola Vermeer, Ronny Drapkin. TRPV1+ sensory innervation as a novel driver of ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR010.

Placental extracellular vesicles promoted cervical tumour tissue undergoing death

BackgroundCervical cancer is a leading cause of death in developing countries. Although the placenta is a tumor-like organ, the placental development, including invasive function, is well controlled. One mechanism is that extracellular vesicles (EVs) released from the placenta contribute to this regulation. Placental EVs carry functional proteins and regulatory RNAs. Our previous study reported that placental EVs inhibited ovarian cancer growth in vitro and in vivo. MethodsWhether the inhibitory effect induced by placental EVs also applies to cervical cancer, a non-endocrine-related cancer, in this study, we first co-cultured the cervical tumour tissues with placental explants. ResultsCo-culturing cervical tumour tissues (n = 7) with placental explants showed necrotic signs and increased levels of senescence-associated proteins and death-associated miRNAs, including miRNA-143-3p, miRNA-519a-5p and miRNA-199a-3p in tumour tissues. Additionally, treatment of HeLa cells with placental EVs reduced the viability of HeLa cells and inhibited the ability of invasion and migration of HeLa cells. Increased levels of senescence-associated proteins and reduced levels of proliferative proteins may contribute to the inhibitory effects in HeLa cells. Discussionplacental EVs are involved in regulating placental development, and the delivery of cargo significantly impacts the functions of target cells. This study found that factors released from placental explants, likely placental EVs, had anti-tumour effects on the cervical tumour by inhibiting cervical cancer cell viability, invasion, and migration. Cargo in placental EVs, such as cellular death-associated miRNAs, may contribute to the inhibitory effects on cervical tumour.

Pharmacological USP2 targeting suppresses ovarian cancer growth by potentiating apoptosis and ferroptosis

Ovarian cancer is a frequently observed type of gynaecologic malignancy generally associated with poor prognosis around the world. Ubiquitin-specific proteases (USPs) form the largest subfamily of deubiquitylating enzymes and have emerged as potential therapeutic targets against human cancers. Through a systematic analysis of the prognostic significance of USP expression, USP2 was found to be inversely correlated with patient survival in ovarian cancer. Accordingly, we investigated the effects of pharmacological inhibition of USP2 on ovarian cancer by exploiting its small molecule inhibitor ML364. Our findings show that ML364 effectively hindered ovarian cancer growth and migration using a series of in vitro assays. In addition to apoptosis induction, ML364 also sensitized ovarian cancer cells to ferroptosis. Mechanistically, ML364 treatment resulted in cyclin D1 downregulation, increased poly (ADP-ribose) polymerase (PARP) cleavage, and elevated ROS levels in ovarian cancer cells. Collectively, our findings suggest USP2 as a potential therapeutic target in ovarian cancer, and hence, its pharmacological inhibition warrants further investigation.

Simple ROS-responsive micelles loaded Shikonin for efficient ovarian cancer targeting therapy by disrupting intracellular redox homeostasis

Ovarian cancer is the most common malignant tumor in women. Shikonin (SHK), an herbal extract from Chinese medicine, shows promise in treating ovarian cancer by inducing reactive oxygen species (ROS). However, its clinical use is limited by poor tumor targeting and low bioavailability, and its therapeutic potential is further compromised by the elevated levels of antioxidants such as glutathione (GSH) within tumor cells. In this study, a novel formulation of ROS-responsive micelles loaded with SHK was developed using hyaluronic acid-phenylboronic acid pinacol ester conjugation (HA-PBAP) for targeted therapy of ovarian cancer through disruption of intracellular redox homeostasis. The SHK@HA-PBAP exhibits targeted delivery to ovarian cancer cells through the interaction between HA and CD44 receptors. Upon internalization by cancer cells, the high levels of intracellular ROS triggered the degradation of SHK@HA-PBAP and simultaneously released SHK and generated GSH scavenger quinone methide (QM). The SHK and QM released from the SHK@HA-PBAP effectively induce the production of ROS and deplete intracellular GSH, leading to the disruption of intracellular redox homeostasis and subsequent induction of cell death. These characteristics collectively inhibit the growth of ovarian cancer. In vitro and in vivo studies have demonstrated that SHK@HA-PBAP micelles exhibit superior antitumor efficacy compared to free SHK in both A2780 cells and A2780 tumor-bearing mice. The ROS-responsive SHK@HA-PBA presents a promising therapeutic approach for the treatment of ovarian cancer.

Y-box binding protein 1/cyclin A1 axis specifically promotes cell cycle progression at G2/M phase in ovarian cancer

Y-box binding protein 1 (YBX1) promotes oncogenic transformation and tumor growth. YBX1 plays a role in regulation of cell cycle promotion via upregulation of cell cycle-related genes. In ovarian cancer, YBX1 also promotes tumor growth, but the mechanisms of YBX1 in cell growth and cell cycle in ovarian cancer remain not to be fully understood. Here, we investigated whether YBX1-dependent cancer cell proliferation was specifically associated with expression of cell cycle related genes in ovarian cancer. Protein and mRNA expression levels of YBX1 and cell cycle-related genes in ovarian cancer cell lines and tissues were determined by western blot analysis, immunohistochemical analysis and reverse transcription-quantitative PCR. Cell cycle analysis was performed by flow cytometry. Luciferase assay and Chromatin immunoprecipitation assay were used to investigate a transcriptional function of YBX1. YBX1 silencing induced marked growth suppression in 4 cell lines (group A), moderate suppression in 5 cell lines (group B), and no suppression in 3 cell lines (group C) among 12 ovarian cancer cell lines in culture. The YBX1 silencing induced cell cycle arrest at G2/M phase and suppressed expression of cyclin A1 gene in group A and B cell lines, but not in group C cell lines. Cyclin A1 silencing specifically suppressed cell proliferation in group A cell lines and partially in group B cell lines, but not at all in group C cell lines. YBX1 mRNA levels were significantly correlated with cyclin A1 mRNA levels in patients with high-grade serous carcinoma. Augmented YBX1 expression plays a key role in tumor growth promotion in ovarian cancer in its close association with cyclin A1.

Tumor targeting peptide TMTP1 modified Antigen capture Nano-vaccine combined with chemotherapy and PD-L1 blockade effectively inhibits growth of ovarian cancer

The mortality of ovarian cancer (OC) has long been the highest among gynecological malignancies. Although OC is considered to be an immunogenic tumor, the effect of immunotherapy is not satisfactory. The immunosuppressive microenvironment is one reason for this, and the absence of recognized effective antigens for vaccines is another. Chemotherapy, as one of the most commonly used treatment for OC, can produce chemotherapy-associated antigens (CAAs) during treatment and show the effect of in situ vaccine. Herein, we designed an antigen capture nano-vaccine NP-TP1@M-M with tumor targeting peptide TMTP1 and dendritic cell (DC) receptor mannose assembled on the surface and adjuvant monophosphoryl lipid A (MPLA) encapsulated in the core of poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles. PLGA itself possessed the ability of antigen capture. TMTP1 was a tumor-homing peptide screened by our research team, which held extensive and excellent tumor targeting ability. After these modifications, NP-TP1@M-M could capture and enrich more tumor-specific antigens after chemotherapy, stimulate DC maturation, activate the adaptive immunity and combined with immune checkpoint blockade to maximize the release of the body’s immune potential, providing an eutherapeutic strategy for the treatment of OC.

A novel selective FAK inhibitor E2 inhibits ovarian cancer metastasis and growth by inducing cytotoxic autophagy

Ovarian cancer (OC) is the deadliest form of the gynecologic malignancies and effective therapeutic drugs are urgently needed. Focal adhesion kinase (FAK) is overexpressed in various solid tumors, and could serve as a potential biomarker of ovarian cancer. However, there are no launched drugs targeting FAK. Hence, the development of the novel FAK inhibitors is an emerging approach for the treatment of ovarian cancer. In this work, we characterized a selective FAK inhibitor E2, with a high inhibitory potency toward FAK. Moreover, E2 had cytotoxic, anti-invasion and anti-migration activity on ovarian cancer cells. Mechanistically, after treatment with E2, FAK downstream signaling cascades (e.g., Src and AKT) were suppressed, thus resulting in the ovarian cancer cell arrest at G0/G1 phase and the induction of cytotoxic autophagy. In addition, E2 attenuated the tumor growth of PA-1 and ES-2 ovarian cancer subcutaneous xenografts, as well as suppressed peritoneal metastasis of OVCAR3-luc. Furthermore, E2 exhibited favorable pharmacokinetic properties. Altogether, these findings demonstrate that E2 is a selective FAK inhibitor with potent anti-ovarian cancer activities both in vivo and in vitro, offering new possibilities for OC treatment strategies.

The TWIK-related acid sensitive potassium 3 (TASK-3) channel contributes to the different effects of anesthetics on the growth and metastasis of ovarian cancer cells

Different anesthetics exert different effects on the long-term outcomes of various cancers. The TWIK-related acid sensitive potassium 3 (TASK-3) channel is an important target of anesthetics and is upregulated in various cancers. However, the role and underlying mechanism of TASK-3 channel in the effects of anesthetics on ovarian cancer remain unknown. Here, we tested whether the TASK-3 channel contributes to the effects of anesthetics on ovarian cancers. We found that the TASK-3 channel was overexpressed in human ovarian cancer and ovarian cancer cell lines. Clinically relevant concentrations of lidocaine, as a TASK-3 channel inhibitor, exert inhibitory effects on tumor growth and metastasis of ovarian cancer cells in vitro and in vivo, whereas the TASK-3 channel potent activator sevoflurane had protumor effects and propofol had no significant effects on tumor growth and metastasis of ovarian cancer. Knockdown of the TASK-3 channel by TASK-3 shRNA attenuated the effects of lidocaine and sevoflurane. Moreover, mitochondrial TASK-3 channel contributes to the effects of lidocaine and sevoflurane on the mitochondrial functions of ovarian cancer. Taken together, the TASK-3 channel, especially the mitochondrial TASK-3 (MitoTASK-3) channel, is a molecular substrate for the effects of lidocaine and sevoflurane on the tumor growth and metastasis of ovarian cancer.

Pixantrone as a novel MCM2 inhibitor for ovarian cancer treatment

BackgroundMini-chromosome maintenance protein 2 (MCM2) is a potential target for the development of cancer therapeutics. However, small molecule inhibitors targeting MCM2 need further investigation. MethodsMolecular dynamics simulation was performed to identify active pockets in the MCM2 protein structure (6EYC). The active pocket was used as a docking model to discover MCM2 inhibitors by using structure-based virtual screening and surface plasmon resonance (SPR) assay. Furthermore, the efficacy of pixantrone targeting MCM2 in ovarian cancer was evaluated in vitro and in vivo. ResultsPixantrone was identified as a novel inhibitor of MCM2 by virtual screening. SPR binding affinity analysis confirmed the direct binding of pixantrone to MCM2 protein. Pixantrone significantly reduced the viability of ovarian cancer cells A2780 and SKOV3 in a dose- and time-dependent manner. In addition, pixantrone inhibited DNA replication, and induced cell cycle arrest and apoptosis in ovarian cancer cells via targeting MCM2. Knockdown of MCM2 could attenuate the inhibitory activity of pixantrone in ovarian cancer cells. Furthermore, pixantrone significantly suppressed ovarian cancer growth in the A2780 cell xenograft mouse model and showed favorable safety. ConclusionThese findings suggest that pixantrone may be a promising drug for ovarian cancer patients by targeting MCM2 in the clinic.

DC-derived CXCL10 promotes CTL activation to suppress ovarian cancer

This study investigates the role of dendritic cells (DCs), with a focus on their CXCL10 marker gene, in the activation of cytotoxic T lymphocytes (CTLs) within the ovarian cancer microenvironment and its impact on disease progression. Utilizing scRNA-seq data and immune infiltration analysis, we identified a diminished DC presence in ovarian cancer. Gene analysis pinpointed CXCL10 as a key regulator in OV progression via its influence on DCs and CTLs. Prognostic analysis and in vitro experiments substantiated this role. Our findings reveal that DC-derived CXCL10 significantly affects CTL activation and proliferation. Reduced CXCL10 levels hinder CTL cytotoxicity, promoting ovarian cancer cell migration and invasion. Experimental studies using animal models have provided further evidence that the capacity of CTLs to suppress tumor development is significantly diminished when treated with DCs that have low expression of CXCL10. Dendritic cell-derived CXCL10 emerges as a pivotal factor in restraining ovarian cancer growth and metastasis through the activation of cytotoxic T lymphocytes. This study sheds light on the crucial interplay within the ovarian cancer microenvironment, offering potential therapeutic targets for ovarian cancer treatment.

Injectable bio-multifunctional hyaluronic acid-based hydrogels loaded with poly ADP-ribose polymerase inhibitors for ovarian cancer therapy

The recent use of PARP inhibitors (PARPi) in the maintenance treatment of ovarian tumor has significantly improved the survival rates of cancer patients. However, the current oral administration of PARP inhibitors fails to realize optimal therapeutic effects due to the low bioavailability in cancerous tissues, and often leads to a range of systemic adverse effects including hematologic toxicities, digestive system reactions, and neurotoxicities. Therefore, the demand for an advanced drug delivery system that can ensure effective drug administration while minimizing these unfavorable reactions is pressing. Injectable hydrogel emerges as a promising solution for local administration with the capability of sustainable drug release. In this study, we developed an injectable hydrogel made from aminated hyaluronic acid and aldehyde-functionalized pluronic127 via Schiff base reaction. This hydrogel exhibits excellent injectability with short gelation time and remarkable self-healing ability, and is applied to load niraparib. The drug-loaded hydrogel (HP@Nir hydrogel) releases drugs sustainably as tested in vitro as well as displays significant anti-proliferation and anti-migratory properties on human epithelial ovarian cancer cell line. Notably, HP@Nir hydrogel effectively suppresses the growth of ovarian cancer, without significant adverse reactions as demonstrated in animal studies. Additionally, the developed hydrogel is gradually degraded in vivo for around 20 d, while maintaining good biocompatibility. Overall, the injectable hydrogel loaded with niraparib provides a secure and efficient strategy for the treatment and management of ovarian cancer.

Single-cell transcriptomics reveals the aggressive landscape of high-grade serous carcinoma and therapeutic targets in tumor microenvironment

High-grade serous carcinoma (HGSC) is characterized by early abdominal metastasis, leading to a dismal prognosis. In this study, we conducted single-cell RNA sequencing on 109,573 cells from 34 tumor samples of 18 HGSC patients, including both primary tumors and their metastatic sites. Our analysis revealed a distinct S100A9+ tumor cell subtype present in both primary and metastatic sites, strongly associated with poor overall survival. This subtype exhibited high expression of S100A8, S100A9, ADGRF1, CEACAM6, CST6, NDRG2, MUC4, PI3, SDC1, and C15orf48. Individual knockdown of these ten marker genes, validated through in vitro and in vivo models, significantly inhibited ovarian cancer growth and invasion. Around S100A9+ tumor cells, a population of HK2+_CAF was identified, characterized by activated glycolysis metabolism, correlating with shorter overall survival in patients. Notably, similar to CAFs, immunosuppressive tumor-associated macrophage (TAM) subtypes underwent glycolipid metabolism reprogramming via PPARgamma regulation, promoting tumor metastasis. These findings shed light on the mechanisms driving the aggressiveness of HGSC, offering crucial insights for the development of novel therapeutic targets against this formidable cancer.

The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer.

Acetyl-CoAacyltransferase2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway that catalyzes the final step of mitochondrial β oxidation, which plays an important role in fatty acid metabolism. The expression of ACAA2 is closely related to the occurrence and malignant progression of tumors. However, the function of ACAA2 in ovarian cancer is unclear. The expression level and prognostic value of ACAA2 were analyzed by databases. Gain and loss of function were carried out to explore the function of ACAA2 in ovarian cancer. RNA-seq and bioinformatics methods were applied to illustrate the regulatory mechanism of ACAA2. ACAA2 overexpression promoted the growth, proliferation, migration, and invasion of ovarian cancer, and ACAA2 knockdown inhibited the malignant progression of ovarian cancer as well as the ability of subcutaneous tumor formation in nude mice. At the same time, we found that OGT can induce glycosylation modification of ACAA2 and regulate the karyoplasmic distribution of ACAA2. OGT plays a vital role in ovarian cancer as a function of oncogenes. In addition, through RNA-seq sequencing, we found that ACAA2 regulates the expression of DIXDC1. ACAA2 regulated the malignant progression of ovarian cancer through the WNT/β-Catenin signaling pathway probably. ACAA2 is an oncogene in ovarian cancer and has the potential to be a target for ovarian cancer therapy.