Glycolysis In Ovarian Cancer Cells Research Articles

Inhibition of ACSS2 triggers glycolysis inhibition and nuclear translocation to activate SIRT1/ATG5/ATG2B deacetylation axis, promoting autophagy and reducing malignancy and chemoresistance in ovarian cancer

BackgroundMetabolic reprogramming is a hallmark of cancer, characterized by a high dependence on glycolysis and an enhanced utilization of acetate as an alternative carbon source. ACSS2 is a critical regulator of acetate metabolism, playing a significant role in the development and progression of various malignancies. ACSS2 facilitates the conversion of acetate to acetyl-CoA, which participates in multiple metabolic pathways and functions as an epigenetic regulator of protein acetylation, thereby modulating key cellular processes such as autophagy. However, the roles and intrinsic connections of ACSS2, glycolysis, protein acetylation, and autophagy in ovarian cancer (OC) remain to be elucidated. Basic proceduresUtilizing clinical specimens and online databases, we analysed the expression of ACSS2 in OC and its relationship with clinical prognosis. By knocking down ACSS2, we evaluated its effects on the malignant phenotype, acetate metabolism, glycolysis, and autophagy. The metabolic alterations in OC cells were comprehensively analysed using Seahorse assays, transmission electron microscopy, membrane potential measurements, and stable-isotope labeling techniques. CUT&TAG and co-immunoprecipitation techniques were employed to explore the deacetylation of autophagy-related proteins mediated by ACSS2 via SIRT1. Additionally, through molecular docking, transcriptome sequencing, and metabolomics analyses, we validated the pharmacological effects of paeonol on ACSS2 and the glycolytic process in OC cells. Finally, both in vitro and in vivo experiments were performed to investigate the impact of paeonol on autophagy and its anti-OC effects mediated through the ACSS2/SIRT1 deacetylation axis. Main findingsACSS2 is significantly upregulated in OC and is associated with poor prognosis. Knockdown of ACSS2 inhibits OC cells proliferation, migration, invasion, angiogenesis, and platinum resistance, while reducing tumour burden in vivo. Mechanistically, inhibiting ACSS2 reduces acetate metabolism and suppresses glycolysis by targeting HXK2. This glycolytic reduction promotes the translocation of ACSS2 from the cytoplasm to the nucleus, leading to increased expression of the deacetylase SIRT1. SIRT1 mediates the deacetylation of autophagy-related proteins, such as ATG5 and ATG2B, thereby significantly activating autophagy in OC cells and exerting antitumor effects. Paeonol inhibits acetate metabolism and glycolysis in OC cells by targeting ACSS2. Paeonol activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation axis, demonstrating inhibition of OC in vitro and in vivo. Principal conclusionsPae can serve as an effective, low-toxicity, multi-targeted drug targeting ACSS2 and glycolysis. It activates autophagy through the ACSS2/SIRT1/ATG5/ATG2B deacetylation signalling cascade, thereby exerting anti-OC effects. Our study provides new insights into the malignant mechanisms of OC and offers a novel strategy for its treatment.

Agrimonolide inhibits glycolysis in ovarian cancer cells by regulating HIF1A

BackgroundOvarian cancer is one of the most common tumors affecting females, significantly disrupting their quality of life. Agrimonolide, an extract derived from Agrimony (Agrimonia pilosa Ledeb.), has been shown to exert various regulatory effects on several diseases. Notably, recent studies indicate that Agrimonolide may attenuate the progression of ovarian cancer. However, the detailed regulatory mechanisms of Agrimonolide in this context require further investigation. PurposeTo determine the significance of HIF1A as a key target in ovarian cancer and its potential underlying signaling pathway. MethodsCell viability and proliferation were assessed using CCK-8 and colony formation assays. Glucose uptake and lactate production were measured using commercial kits, and the extracellular acidification rate (ECAR) was evaluated. Protein expression levels were analyzed through western blotting. ResultsOur network pharmacology analysis identified HIF1A as a crucial target and signaling pathway in ovarian cancer. Furthermore, treatment with Agrimonolide (20μM and 40μM) inhibited the growth of ovarian cancer cells. Agrimonolide also reduced glycolytic activity in these cells. Additionally, Agrimonolide treatment led to decreased expression levels of HIF1A, HK2, and LDHA in ovarian cancer cells. Rescue assays revealed that glucose uptake and lactate production were diminished following Agrimonolide treatment; however, these effects were reversed upon overexpression of HIF1A. ConclusionThis study showed that Agrimonolide can suppress glycolysis in ovarian cancer cells by modulating HIF1A, supporting Agrimonolide as a promising therapeutic agent for ovarian cancer treatment.

Xanthohumol Promotes Skp2 Ubiquitination Leading to the Inhibition of Glycolysis and Tumorigenesis in Ovarian Cancer.

Ovarian cancer is a common, highly lethal tumor. Herein, we reported that S-phase kinase-associated protein 2 (Skp2) is essential for the growth and aerobic glycolysis of ovarian cancer cells. Skp2 was upregulated in ovarian cancer tissues and associated with poor clinical outcomes. Using a customized natural product library screening, we found that xanthohumol inhibited aerobic glycolysis and cell viability of ovarian cancer cells. Xanthohumol facilitated the interaction between E3 ligase Cdh1 and Skp2 and promoted the Ub-K48-linked polyubiquitination of Skp2 and degradation. Cdh1 depletion reversed xanthohumol-induced Skp2 downregulation, enhancing HK2 expression and glycolysis in ovarian cancer cells. Finally, a xenograft tumor model was employed to examine the antitumor efficacy of xanthohumol in vivo. Collectively, we discovered that xanthohumol promotes the binding between Skp2 and Cdh1 to suppress the Skp2/AKT/HK2 signal pathway and exhibits potential antitumor activity for ovarian cancer cells.

Interference with MTHFD2 induces ferroptosis in ovarian cancer cells through ERK signaling to suppress tumor malignant progression.

Ovarian cancer (OC) is a deadliest gynecological cancer with the highest mortality rate. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a crucial tumor-promoting factor, is over-expressed in several malignancies including OC. The present study aimed to explore the role and mechanisms of MTHFD2 in OC malignant progression. Thus, cell proliferation, cycling, apoptosis, migration, and invasion were evaluated by CCK-8 assay, EdU assay, flow cytometry, wound healing, transwell assay and western blotting. Additionally, glycolysis was assessed by measuring the level of glucose and lactate production, as well as the expressions of GLUT1, HK2 and PKM2. Then the expression of ferroptosis-related proteins and ERK signaling was detected using western blotting. Ferroptosis was detected through the measurement of iron level, GSH, MDA and ROS activities. The results revealed that MTHFD2 was highly expressed in OC cells. Besides, interference with MTHFD2 induced ferroptosis, promoted ROS accumulation, destroyed mitochondrial function, reduced ATP content and inhibited glycolysis in OC cells. Subsequently, we further found that interference with MTHFD2 affected mitochondrial function and glycolysis in OC cells through ERK signaling. Moreover, interference with MTHFD2 affected ferroptosis to inhibit the malignant progression of OC cells. Collectively, our present study disclosed that interference with MTHFD2 induced ferroptosis in OC to inhibit tumor malignant progression through regulating ERK signaling.

MiR-19a-3p Promotes Aerobic Glycolysis in Ovarian Cancer Cells via IGFBP3/PI3K/AKT Pathway.

Aerobic glycolysis is a prominent feature of cancer. Here, we reported that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells SKVO3 and ES-2 by increased production of ATP, lactic acid, extracellular acidification (ECAR), and increased expression of PKM2, LDHA, GLUT1 and GLUT3. Further study showed that over-expression of IGFBP3, the target of miR-19a-3p, decreases aerobic glycolysis in ovarian cancer cells, while knockdown of IGFBP3 expression increases aerobic glycolysis. The rescue assay suggested that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through targeting IGFBP3. Moreover, over-expression of miR-19a-3p or silencing of IGFBP3 expression promoted activation of AKT, which is important for aerobic glycolysis in cancer cells, indicating that miR-19a-3p promotes aerobic glycolysis in ovarian cancer cells through the IGFBP3/PI3K/AKT pathway. This suggests that miR-19a-3p and IGFBP3 may serve as potential treatment targets of ovarian cancer.

MiR-194-5p suppresses the warburg effect in ovarian cancer cells through the IGF1R/PI3K/AKT axis

Background: The Warburg effect is considered as a hallmark of various types of cancers, while the regulatory mechanism is poorly understood. Our previous study demonstrated that miR-194-5p directly targets and regulates insulin-like growth factor1 receptor (IGF1R). In this study, we aimed to investigate the role of miR-194-5p in the regulation of the Warburg effect in ovarian cancer cells. Methods: The stable ovarian cell lines with miR-194-5p overexpression or silencing IGF1R expression were established by lentivirus infection. ATP generation, glucose uptake, lactate production and extracellular acidification rate (ECAR) assay were used to analyze the effects of aerobic glycolysis in ovarian cancer cells. Gene expression was analyzed by quantitative polymerase chain reaction (qPCR) and western blot. Immunohistochemistry assays were performed to assess the expression of the IGF1R protein in ovarian cancer tissues. Results: Overexpression of miR-194-5p or silencing IGF1R expression in ovarian cancer cells decreases ATP generation, glucose uptake, lactate production, and ECAR and inhibits both the mRNA and protein expression of PKM2, LDHA, GLUT1, and GLUT3. While the knockdown of miR-194-5p expression led to opposite results. Overexpression of miR-194-5p or silencing IGF1R expression suppressed the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, whose activation can sustain aerobic glycolysis in cancer cells, and the knockdown of miR-194-5p expression promoted the activation of the PI3K/AKT pathway. Conclusion: Our results suggest that miR- 194-5p can inhibit the Warburg effect by negative regulation of IGF1R and further repression of the PI3K/AKT pathway, which provides a theoretical basis for further test of miR-194-5p as a target in the treatment of ovarian cancer.

Glucose deprivation enhances resistance to paclitaxel via ELAVL2/4-mediated modification of glycolysis in ovarian cancer cells.

The dysregulation of glycolysis regardless of oxygen availability is one of the major characteristics of cancer cells. While the drug resistance of ovarian cancer cells has been extensively studied, the molecular mechanism of anticancer drug resistance under low-glucose conditions remains unknown. In this study, we investigated the pathway mediating drug resistance under low-glucose conditions by examining the relationship between embryonic lethal abnormal vision Drosophila homolog-like (ELAVL) protein and glycolysis-related enzymes. Ovarian cancer cells resistant to 2.5 nM paclitaxel were exposed to low-glucose media for 2 weeks, and the expression levels of ELAVL2, ELAVL4, glycolytic enzymes, and drug resistance-related proteins were elevated to levels comparable to those in cells resistant to 100 nM paclitaxel. Gene silencing of ELAVL2/4 using small interfering RNA prevented the upregulation of glycolysis-related enzymes, reduced lactate production, and sensitized 2.5 nM paclitaxel-resistant ovarian cancer cells to anticancer agents under hypoglycemic conditions. Furthermore, pharmacological inhibition of glycolytic enzymes with 2-deoxyglucose, a specific inhibitor of glycolysis, triggered caspase-dependent apoptosis, reduced lactate generation, and blocked the expression of drug resistance-related proteins under low-glucose conditions. These results suggest that the level of ELAVL2/4 is responsible for the development of chemoresistance through activation of the glycolysis pathway under glucose deprivation conditions.

The role of S-nitrosylation of PFKM in regulation of glycolysis in ovarian cancer cells

One of the malignant transformation hallmarks is metabolism reprogramming, which plays a critical role in the biosynthetic needs of unchecked proliferation, abrogating cell death programs, and immunologic escape. However, the mechanism of the metabolic switch is not fully understood. Here, we found that the S-nitrosoproteomic profile of endogenous nitrogen oxide in ovarian cancer cells targeted multiple components in metabolism processes. Phosphofructokinase (PFKM), one of the most important regulatory enzymes of glycolysis, was S-nitrosylated by nitric oxide synthase NOS1 at Cys351. S-nitrosylation at Cys351 stabilized the tetramer of PFKM, leading to resist negative feedback of downstream metabolic intermediates. The PFKM-C351S mutation decreased the proliferation rate of cultured cancer cells, and reduced tumor growth and metastasis in the mouse xenograft model. These findings indicated that S-nitrosylation at Cys351 of PFKM by NOS1 contributes to the metabolic reprogramming of ovarian cancer cells, highlighting a critical role of endogenous nitrogen oxide on metabolism regulations in tumor progression.

Bcl2 inhibitor ABT737 reverses the Warburg effect via the Sirt3-HIF1α axis to promote oxidative stress-induced apoptosis in ovarian cancer cells

AimsCompared to normal cells, tumor cells maintain higher concentrations of reactive oxygen species (ROS) to support proliferation, invasion, and metastasis. Chemotherapeutic drugs often induce tumor cell apoptosis by increasing intracellular ROS concentrations to highly toxic levels. ABT737, which inhibits the apoptosis regulator B cell lymphoma 2 (Bcl2), increases the sensitivity of ovarian cancer cells to chemotherapeutic drugs by regulating the glucose metabolism, but the underlying mechanisms remain unclear. Therefore, we aimed to determine whether ABT737 promoted H2O2-induced tumor cell apoptosis by reversing glycolysis in ovarian cancer cells. Main methodsSKOV3 ovarian cancer cells were treated with H2O2, ABT737, or both. Cell viability was compared using methyl thiazolyl tetrazolium (MTT), and flow cytometry was used to detect differences in apoptosis, ROS, and mitochondrial membrane potential. The relative expression levels of proteins associated with apoptosis and the glucose metabolism were measured using immunoblotting. Finally, glucose uptake and lactate secretion were measured using kits and compared. Key findingsABT737 downregulated proteins associated with glucose uptake (GLUT1) and glycolysis (LHDA, PKM2 and HK2) via the Sirt3-HIF1α axis, reducing glucose uptake and lactate secretion in SKOV3 cells. This reversed glycolysis in the tumor cells, and promoted H2O2-induced apoptosis. SignificanceThe Bcl2 inhibitor ABT737 enhanced the anti-tumor effect of oxidative stress by reversing the Warburg effect in ovarian cancer cells, providing powerful theoretical support for further clinical applications of Bcl2 inhibitors.

Probing Metabolic Changes in IFNγ-Treated Ovarian Cancer Cells.

Interferon-γ (IFNγ) is a pleiotropic cytokine that signals to many different cell types. IFNγ has both antitumor functions and pro-tumorigenic effects and regulates different aspects of cell physiology, including metabolism. Cancer cells undergo a complex rearrangement of metabolic pathways that allows them to satisfy the needs of increased proliferation, and many cancer cells redirect glucose metabolism from oxidative phosphorylation to aerobic glycolysis. In this chapter, we describe a protocol that utilizes the Agilent Seahorse XFp Analyzer to assess mitochondrial respiration and glycolysis in ovarian cancer cells treated with IFNγ.

Long non-coding RNA LINC00504 regulates the Warburg effect in ovarian cancer through inhibition of miR-1244.

Ovarian cancer (OC) is the most lethal gynecologic malignancy and long non-coding RNAs (lncRNAs) have been acknowledged as important regulators in human OC. This study aimed to investigate the function and underlying mechanisms of LINC00504 in OC. The expression levels of LINC00504 in human OC tissues and cell lines were investigated by qRT-PCR analysis. The OC cell proliferation, and apoptosis were evaluated by MTT assay, colony-formation assay, Caspase-3 activity assay, and nucleosome ELISA assay, respectively. The metabolic shift in OC cells was examined by aerobic glycolysis analysis. Dual-luciferase activity reporter assay and mRNA-miRNA pull-down assay were conducted to validate the interaction between LINC00504 and miR-1244. LINC00504 was upregulated in OC cell lines and specimens. Knockdown of LINC00504 inhibited cell proliferation, enhanced apoptosis, decreased glycolysis-related gene (PKM2, HK2, and PDK1) expression, and altered aerobic glycolysis in OC cells and vice versa. LINC00504 downregulated miR-1244 expression levels by acting as an endogenous sponge of miR-1244. Inhibition of miR-1244 diminished the effects of LINC00504 on OC cells. Our study shows that LINC00504 promotes OC cell progression and stimulates aerobic glycolysis by interacting with miR-1244, which indicates that LINC00504 might act as a promising therapeutic target for OC treatment.

ACTL6A regulates follicle-stimulating hormone-driven glycolysis in ovarian cancer cells via PGK1

Enhanced glycolysis has been identified as a hallmark of cancer. As a novel oncogene, ACTL6A is aberrantly amplified in several types of human cancers and has been shown to regulate tumor growth and progression. However, the roles of ACTL6A in the development of ovarian cancer and the regulation of cancer glucose metabolism are mostly unknown. Here we show that ACTL6A is overexpressed in ovarian cancers compared with adjacent non-tumor tissues, and that ACTL6A overexpression correlates with poor prognosis. Silencing of ACTL6A in vitro inhibits proliferation, clonal growth, and migration, and decreases glucose utilization, lactate production, and pyruvate levels of ovarian cancer cells. We found a positive correlation between ACTL6A and PGK1 expression in ovarian cancer tissues. Enforced ACTL6A expression increased PGK1 expression, whereas knockdown of ACTL6A had the opposite effect. Altered ACTL6A expression inhibits the tumorigenicity of ovarian cancer cells in vivo by downregulating PGK1. In addition, the expression of ACTL6A is regulated by follicle-stimulating hormone (FSH) stimulation via PI3K/AKT pathway. Importantly, ACTL6A regulates FSH-enhanced glycolysis in ovarian cancer. Taken together, our findings highlight the critical role of ACTL6A in ovarian cancer development and identify its contribution to glucose metabolism of cancer cells.

Apatinib inhibits glycolysis by suppressing the VEGFR2/AKT1/SOX5/GLUT4 signaling pathway in ovarian cancer cells

BackgroundApatinib is a tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2 (VEGFR2), and has shown encouraging therapeutic effects in various malignant tumors. As yet, however, the role of apatinib in ovarian cancer has remained unknown. Here, we sought to elucidate the role of apatinib in the in vitro and in vivo viability and proliferation of ovarian cancer cells, as well as in glucose metabolism in these cells.MethodsThe effects of apatinib on ovarian cancer cell viability and proliferation were assessed using Cell Counting Kit-8 (CCK-8) and colony formation assays, respectively. The expression of VEGFR2/AKT1/SOX5/GLUT4 pathway proteins was assessed using Western blotting, and glucose uptake and lactate production assays were used to detect glycolysis in ovarian cancer cells. SOX5 was exogenously over-expressed and silenced in ovarian cancer cells using expression vector and shRNA-based methods, respectively. RNA expression analyses were performed using RNA-seq and gene-chip-based methods. GLUT4 promoter activity was assessed using a dual-luciferase reporter assay. The expression of p-VEGFR2 (Tyr1175), p-AKT1 (Ser473), p-GSK3β (Ser9), SOX5 and GLUT4 in xenograft tissues was assessed using immunohistochemistry (IHC).ResultsWe found that apatinib inhibited the in vitro and in vivo viability and proliferation in Hey and OVCA433 ovarian cancer cells in a dose-dependent and time-dependent manner. We also found that apatinib effectively suppressed glucose uptake and lactate production by blocking the expression of GLUT4 in these cells. In addition, we found that SOX5 predominantly rescued the inhibitory effect of apatinib on GLUT4 expression by activating its promoter. Finally, we found that apatinib regulated the expression of SOX5 by suppressing the VEGFR2/AKT1/GSK3β signaling pathway.ConclusionsFrom our results, we conclude that apatinib suppresses the in vitro and in vivo viability and proliferation of ovarian cancer cells, as well as glycolysis by inhibiting the VEGFR2/AKT1/GSK3β/SOX5/GLUT4 signaling pathway. Apatinib may serve as a promising drug for the treatment of ovarian cancer.

MiR-1180 from bone marrow MSCs promotes cell proliferation and glycolysis in ovarian cancer cells via SFRP1/Wnt pathway

BackgroundThe ovarian cancer microenvironment is responsible for cancer cell growth and disease relapse. Bone marrow mesenchymal stem cells (BM-MSCs) play important roles in ovarian cancer, however, the mechanism of BM-MSCs inducing cell proliferation and glycolysis needs further research.MethodsmiRNA array was used to analyze the significant miRNAs. RT-qPCR was used to examine the level of miR-1180 and SFRP1. The western blotting was used to detect the protein level of SFRP1 and Wnt signal pathway. We utilized luciferase reporter assay to confirm the direct interaction of SFRP1 with miR-1180. MTT assay were employed to investigate the proliferation of ovarian cancer cells. ECAR, ATP assay were used to measure the glycolysis state of ovarian cancer cells.ResultsIt was demonstrated that BM-MSCs promoted ovarian cancer cell proliferation and glycolysis. The miRNA profile from the BM-MSCs indicated that miR-1180 was up-regulated in the conditioned medium of BM-MSCs. MiR-1180 could accelerate ovarian cancer cell proliferation and glycolysis. We also found that up-regulation of miR-1180 activated Wnt signaling by targeting SFRP1 in ovarian cancer cells.ConclusionThe study demonstrated that miR-1180 was a critical miRNA mediating BM-MSCs induced cell proliferation and glycolysis and could be a new target in ovarian cancer therapy.

Pim1 promotes cell proliferation and regulates glycolysis via interaction with MYC in ovarian cancer.

BackgroundOvarian cancer (OC) is the leading cause of death among women with gynecologic malignancies. Recent studies have highlighted the role of Pim1, which belongs to a group of constitutively activated serine/threonine kinases, in cancer development. However, the effect of Pim1 in OC is largely unclear.MethodsOC cell lines with Pim1 overexpression or knockdown were constructed with len-tivirus transduction. Cell Counting Kit-8, colony formation, glycolysis stress test and in vivo mice models were carried out to assess the effect of Pim1 on OC biological functions. Co-immunoprecipitation assay coupled with western blot were performed to explore the intrinsic mechanisms of Pim1 in OC. Bioinformatic analysis was then performed to evaluate the expression and prognostic value of Pim1.ResultsWe present the first evidence that silencing or overexpressing Pim1 can suppress or promote, respectively, OC cell proliferation. Furthermore, we demonstrated that Pim1 can significantly enhance glycolysis in OC cells. In vivo experiments further confirmed that knockdown of Pim1 inhibits the growth of tumors derived from the SKOV3 cell line. To search for the underlying molecular mechanism, we examined the effect of Pim1 on MYC, a pivotal gene in glycolysis, and observed that Pim1-mediated phosphorylation of c-Myc activated the expression of glycolysis-associated key genes such as PGK1 and LDHA. Moreover, we found that the Pim1 inhibitor SMI4a induced chemosensitization to cisplatin. Clinically, Pim1 was also overexpressed in OC and correlated with poor overall survival by bioinformatics analysis.ConclusionTogether, these results suggest that Pim1 contributes to proliferation and gly-colysis in OC via interaction with MYC and may serve as a potential target in the treatment of OC patients.

Abstract 5420: PGAM1-REDD1 pathway promotes paclitaxel resistance through enhancing aerobic glycolysis in ovarian cancer cells

Abstract Aerobic glycolysis is a dominant pathway for energy production in cancer cells, but the association of this phenomenon with chemoresistance remains still uncertain. Here, we found that the expression of phosphoglycerate mutase 1 (PGAM1), a key catalytic enzyme in aerobic glycolysis, was significantly higher in paclitaxel-resistant ovarian cancer cell line SKOV3. Up-regulated PGAM1 expression by gene transfection and down-regulated PGAM1 expression by siRNA knockdown altered the process of aerobic glycolysis, paclitaxel sensitivity and DNA damage response 1 (REDD1) expression in ovarian cancer cells (SKOV3 and A2780). Further, the change of the concentration of pyruvic acid or lactic acid in culture medium and REDD1 expression by gene transfection or siRNA knockdown also altered the sensitivity to paclitaxel. REDD1 knockdown of by siRNA reversed partially paclitaxel resistance induced by PGAM1 over-expression in cancer cells, vice versa. Structural interaction between PGAM1 and REDD1 was predicted by molecular docking. Our results suggested that PGAM1-REDD1 pathway promotes paclitaxel resistance through enhancing aerobic glycolysis in ovarian cancer cells. Citation Format: Yan Feng, Weiguo Lv, Xing Xie, Yan Yu. PGAM1-REDD1 pathway promotes paclitaxel resistance through enhancing aerobic glycolysis in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5420. doi:10.1158/1538-7445.AM2017-5420

TNFR1 Regulates Ovarian Cancer Cell Tumorigenicity Through PIK3CB-p110Beta.

Studies have shown that TNFR1 is a key factor in the tumor microenvironment that is dependent on the TNF-α-initiated cascade for tumorigenesis. In this present study, we found that TNFR1 is over-expressed in ovarian cancer, which is relevant to both clinical survival and disease free status. Knockdown of TNFR1 dramatically attenuates malignant phenotypes, including proliferation and colony growth in soft agar, as well as glycolysis in ovarian cancer cells. Unexpectedly, knocking down TNFR1 blocks EGF-induced p-AKT and p-p70S6K expression and EGF-induced cell transformation through PIK3-p110beta rather than p110alpha expression. Taken together, our data provide evidence that TNFR1 plays a critical role in ovarian cancer and show that the EGF induced signaling pathway is independent of the TNF-α triggering cascade signal. Therefore, TNFR1 may serve as a prognostic molecule in ovarian cancer.

Ginsenoside 20(S)‑Rg3 inhibits the Warburg effect through STAT3 pathways in ovarian cancer cells.

Cancer cells prefer to metabolize glucose through aerobic glycolysis, known as the Warburg effect. It plays a crucial role in proliferation and progression of cancer cells. However, the complete mechanism remains elusive. In recent studies, the signal transducer and activator of transcription 3 (STAT3) signaling has been discovered to have roles in cancer‑associated changes in metabolism. In this study, we find that the ginsenoside 20(S)‑Rg3, a pharmacologically active component of the traditional Chinese herb Panax ginseng, inhibits glycolysis in ovarian cancer cells by regulating hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2). We also show that 20(S)‑Rg3 regulates HK2 through downregulation of p‑STAT3 (Tyr705). Furthermore, overexpression of STAT3 in ovarian cancer cells weakened the suppression of Warburg effect induced by 20(S)‑Rg3. Importantly, 20(S)‑Rg3 treatment represses HK2 expression in nude mouse xenograft models of ovarian cancer. Taken together, our results show that 20(S)‑Rg3 inhibits the Warburg effect by targeting STAT3/HK2 pathway in ovarian cancer cells, highlighting the potentiality of 20(S)‑Rg3 to be used as a therapeutic agent for ovarian cancer.