Glycolysis In Ovarian Cancer Research Articles

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.

SMAD4 inhibits glycolysis in ovarian cancer through PI3K/AKT/HK2 signaling pathway by activating ARHGAP10.

ARHGAP10 is a tumor-suppressor gene related to ovarian cancer (OC) progression; however, its specific mechanism is unclear. To investigate the effect of ARHGAP10 on OC cell migration, invasion, and glycolysis. Quantitative real-time PCR (qRT-PCR) quantified mRNA and protein expressions of AKT, p-AKT, HK2, and SMAD4 were tested by Western blot. EdU, Wound healing, and Transwell assay were utilized to evaluate OC cell proliferation, migration, and invasion. We used a Seahorse XF24 Extracellular Flux Analyzer to monitor cellular oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Chromatin immunoprecipitation (ChIP) was used to analyze the transcriptional regulation of ARHGAP10 by SMAD4. ARHGAP10 expression in OC tissues was detected by immunohistochemistry. Our results showed that ARHGAP10 expression was negatively related to lactate levels in human OC tissues. ARHGAP10 overexpression can inhibit the migration, proliferation, and invasion of OC cells, and this function can be blocked by 2-Deoxy-D-glucose. Moreover, we found that ARHGAP10 expression can be rescued with the AKT inhibitor LY294002. This study revealed that the antitumor effects of ARHGAP10 in vivo and in vitro possibly suppress oncogenic glycolysis through the PI3K/AKT/HK2-regulated glycolysis metabolism pathway.

Research progress on the mechanism of glycolysis in ovarian cancer.

Glycolysis is the preferred energy metabolism pathway in cancer cells even whenthe oxygen content is sufficient. Through glycolysis, cancer cells convert glucose into pyruvic acid and then lactate to rapidly produce energy and promote cancer progression. Changes in glycolysis activity play a crucial role in the biosynthesis and energy requirements of cancer cells needed to maintain growth and metastasis. This review focuses on ovarian cancer and the significance of key rate-limiting enzymes (hexokinase, phosphofructokinase, and pyruvate kinase, related signaling pathways (PI3K-AKT, Wnt, MAPK, AMPK), transcription regulators (HIF-1a), and non-coding RNA in the glycolytic pathway. Understanding the relationship between glycolysis and these different mechanisms may provide new opportunities for the future treatment of ovarian cancer.

MiR-532–3p suppresses proliferation and invasion of ovarian cancer cells via GPNMB/HIF-1α/HK2 axis

ObjectiveIdentifying a new target of miR-532–3p and studying its functional mechanism to explore the detailed anti-tumor mechanism of miR-532–3p in ovarian cancer. MethodsBiological and molecular methods including real-time quantitative PCR (RT-qPCR), Western blotting, colony formation, in vitro migration and invasion assays, glucose consumption and lactate production assays, RNA interference and tumor xenograft mouse models were used to study the role of miR-532–3p and its target in ovarian cancer. mRNA sequencing, dual-luciferase reporter assay and immunohistochemistry (IHC) were used to identify miR-532–3p target. STRING dataset analysis, qPCR and Western blotting were used to investigate the downstream pathway of the target of miR-532–3p. ResultsForced expression of miR-532–3p inhibited the proliferation, migration and invasion of ovarian cancer cells in vitro and the tumor growth in nude mice. RNA sequencing found 299 mRNAs were downregulated in miR-532–3p-overexpressed ovarian cancer cells, and bioinformatic analysis indicated Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB), a type I membrane glycoprotein, was the potential target of miR-532–3p. GPNMB was reduced at both RNA and protein levels in miR-532–3p-overexpressed ovarian cancer cells. Dual-luciferase reporter assay determined GPNMB as the target of miR-532–3p. Interference of GPNMB inhibited the proliferation, migration, invasion, glucose consumption and lactate production of ovarian cancer cells. Knocking down of GPNMB reduced the protein level of HIF-1α without affecting HIF-1α mRNA level. Overexpression of GPNMB reversed the antitumor effect of miR-532–3p. ConclusionmiR-532–3p exerted the anti-cancer effect by targeting GPNMB/ HIF-1α/ HK2 pathway to inhibit aerobic glycolysis in ovarian cancer.

MFAP2 aggravates tumor progression through activating FOXM1/β-catenin-mediated glycolysis in ovarian cancer.

Ovarian cancer is one of the most common gynecological tumors that seriously endanger the health and quality of life of women. Microfibril-associated protein 2 (MFAP2) has been demonstrated to play crucial roles in the development of multiple tumors. However, the function of MFAP2 in ovarian cancer remains unclear. In this study, we found that MFAP2 was upregulated in ovarian cancer and cells and was positively correlated with FOXM1 and glycolysis-related genes. The results of Cell Count Kit-8, colony formation, and flow cytometry assays indicated that MFAP2 promoted cell proliferation. In addition, MFAP2 promotes cell proliferation, glucose uptake, lactate production; increases ATP levels, extracellular acidification ratio, and oxygen consumption ratio in ovarian cancer cells and increases the expression of glycolytic proteins. Further mechanistic analysis suggests that MFAP2 promotes FOXM1/β-catenin-mediated glycolysis signaling in ovarian cancer cells. Knockdown of MFAP2 inhibits ovarian cancer xenograft tumor growth and expression of Ki-67, MFAP2, FOXM1, GLUT1, HK2, and β-catenin in mice. In conclusion, MFAP2 promotes cell proliferation and glycolysis by modulating the FOXM1/β-catenin signaling pathway in ovarian cancer, which may offer a fresh insight into the treatment of ovarian cancer in the glycolysis pathway.

Propofol modulates glycolysis reprogramming of ovarian tumor via restraining circular RNA-zinc finger RNA-binding protein/microRNA-212-5p/superoxide dismutase 2 axis

ABSTRACT Metabolic reprogramming refers to the transformation of the whole metabolic network covering glycolysis and mitochondrial metabolism, which is primarily manifested as the Warburg effect and mitochondrial metabolic reprogramming. Propofol (Pro) has been testified to suppress the malignancy of diversified human cancers. Nevertheless, its role in glycolysis is still uncertain. The purpose of this study was to determine whether Pro modulated glycolysis in ovarian cancer (OC) cells. Cell proliferation, apoptosis, migration, and invasion were tested via CCK-8, flow cytometry, and Transwell assays, respectively, and glucose intake, lactic acid, and ATP production were also determined. Pro restrained glycolysis via mediating the circular RNA-zinc finger RNA-binding protein (ZFR)/microRNA (miR)-212-5p/superoxide dismutase 2 (SOD2) axis. Additionally, Pro restrained cancer cell advancement via modulating circ-ZFR/miR-212-5p/SOD2 axis. In short, Pro restrained glycolysis via mediating the circ-ZFR/miR-212-5p/SOD2 axis. These results offered a better theoretical foundation for comprehending the molecular pathology of OC and provided a novel target for OC diagnosis and treatment.

Noncoding RNAs in the Glycolysis of Ovarian Cancer.

Energy metabolism reprogramming is the characteristic feature of tumors. The tumorigenesis, metastasis, and drug resistance of ovarian cancer (OC) is dependent on energy metabolism. Even under adequate oxygen conditions, OC cells tend to convert glucose to lactate, and glycolysis can rapidly produce ATP to meet their metabolic energy needs. Non-coding RNAs (ncRNAs) interact directly with DNA, RNA, and proteins to function as an essential regulatory in gene expression and tumor pathology. Studies have shown that ncRNAs regulate the process of glycolysis by interacting with the predominant glycolysis enzyme and cellular signaling pathway, participating in tumorigenesis and progression. This review summarizes the mechanism of ncRNAs regulation in glycolysis in OC and investigates potential therapeutic targets.

Retraction Note to: Resibufogenin suppresses tumor growth and inhibits glycolysis in ovarian cancer by modulating PIM1.

The Editor in Chief retracted this article (1) because of significant concerns regarding a number of Figures presented in this work, which question the integrity of the data.

LncRNA LINC00857 regulates the progression and glycolysis in ovarian cancer by modulating the Hippo signaling pathway

Ovarian cancer is one of the most common gynecological cancers with high morbidity and mortality, which seriously endangers women's health and quality of life. Long noncoding RNAs (lncRNAs) can regulate the progression of cancers, including ovarian cancer. LINC00857 (long intergenic non‐protein coding RNA 857) has been discovered to be a crucial factor in the regulation of cancer development. Nevertheless, the specific functions and mechanisms of LINC00857 in ovarian cancer remain unclear. The Hippo signaling pathway can involve in cancer progression. In our research, we aimed to investigate the correlation of LINC00857 and Hippo pathway. Quantitative real‐time polymerase chain reaction assay was utilized to test the expression of LINC00857 in ovarian cancer tissues and cells. Functional experiments revealed that LINC00857 silencing led to the inhibition on cell proliferation, migration, invasion, and glycolysis but accelerated cell apoptosis in ovarian cancer. Mechanism experiments, including RNA immunoprecipitation, RNA pull‐down, and luciferase reporter experiments demonstrated that LINC00857 could regulate YAP1 (Yes1 associated transcriptional regulator) by competitively binding to miR‐486‐5p in ovarian cancer. In a word, this study unveiled that LINC00857 regulates YAP1 by competitively binding to miR‐486‐5p and accelerates ovarian cancer progression.

TRIM59, amplified in ovarian cancer, promotes tumorigenesis through the MKP3/ERK pathway.

Tripartite motif containing 59 (TRIM59) functions as an oncoprotein in various human cancers including ovarian cancer. In this study, we found that TRIM59 gene amplification was prevalent in ovarian cancer tissues, and its amplification was significantly correlated with poorer overall survival. Moreover, knockdown of TRIM59 in SKOV3 and OVCAR3 cells, which had relatively high level of TRIM59, suppressed glucose uptake and lactate production. TRIM59 knockdown also decreased the expression of c-Myc and lactate dehydrogenase A, and the phosphorylation of extracellular signal-regulated kinase (ERK). TRIM59 overexpression in A2780 cells, which expressed low level of TRIM59, showed reverse effects. Notably, treatment with an ERK inhibitor (PD98059) completely abolished the oncogenic effects of TRIM59 overexpression. Interestingly, TRIM59 increased the ubiquitination of MAP kinase phosphatase 3 (MKP3), which may dephosphorylate and inactivate ERK. Ectopic expression of MKP3 inhibited the promoting effects of TRIM59 on glycolysis and the phosphorylation of ERK. TRIM59 protein expression was negatively correlated with MKP3 protein expression in ovarian cancer tissues. Finally, TRIM59 amplification potently affected the anticancer effect of 3-bromopyruvate, an inhibitor of glycolysis, in ovarian cancer cells and patient-derived xenograft. In conclusion, these results suggest that TRIM59 may regulate glycolysis in ovarian cancer via the MKP3/ERK pathway.

Resibufogenin suppresses tumor growth and inhibits glycolysis in ovarian cancer by modulating PIM1.

Ovarian cancer is a common human malignancy of the female reproductive system. However, chemotherapy has been proven to have limited effectiveness in a majority of patients. Resibufogenin (RB) is a major active ingredient in cinobufacini, which has been used in the treatment of human malignancies as adjunct agents. This study was designed to examine the anti-cancer effect of RB and the underlying mechanisms in ovarian cancer. Our results showed that RB treatment resulted in cell death, cell cycle arrest, and apoptosis in ovarian cancer cells. The anti-growth and pro-apoptotic effects of RB were also validated in xenograft mice models. Proteomics analysis indicated that RB was able to alter the expressions of several genes, which were involved in the regulation of glycolysis. The suppression effect of RB in the glycolysis pathway of ovarian cancer cells was validated by decreased glucose consumption, lactate production, and extracellular acidification rate (ECAR). We proposed that PIM1 functioned as the key target that mediated the anti-cancer effect of RB against ovarian cancer cells. Our results have revealed that RB downregulated PIM1 in ovarian cancer cells and its downstream genes involved in glycolysis. Moreover, our results indicated that the anti-growth activities and suppressing effect of RB on glycolysis were enhanced significantly by PIM1 knockdown but was attenuated by ectopic PIM1 expression. This provided evidence to support the role of PIM1 in the anti-cancer activities of RB.

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.

Long non-coding RNA GEHT1 promoted the proliferation of ovarian cancer cells via modulating the protein stability of HIF1α.

Cancer cells preferentially metabolize glucose via the aerobic glycolysis pathway, which is also named as Warburg effect. Increasing evidence has suggested that suppression of glycolysis inhibits the progression of cancers. In the present study, we found that the long non-coding RNA gastric carcinoma high expressed transcript 1 (GHET1) was overexpressed in ovarian cancer tissues and cell lines. Up-regulation of GHET1 was positively correlated with the tumor size and metastasis of the ovarian cancer patients. Overexpression of GEHT1 significantly promoted the proliferation and colony formation of ovarian cancer cells. Mechanistically, the candidate binding partners of GHET1 were explored by pull-down and mass spectrum. Of note, GHET1 was found to interact with the E3 ubiquitin ligase von Hippel-Lindau (VHL), which consequently blocked VHL-mediated degradation of hypoxia-inducible factor-1α (HIF1α) and enhanced the protein level of HIF1α in ovarian cancer cells. The up-regulated HIF1α promoted the glucose uptake and lactate generation of ovarian cancer cells. Collectively, our results suggested the oncogenic function of GHET1 via up-regulating the glycolysis in ovarian cancer and can be considered as a promising anti-cancer target.

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.

MICU1 drives glycolysis and chemoresistance in ovarian cancer

Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca2+ uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show that MICU1 is overexpressed in a panel of ovarian cancer cell lines and that MICU1 overexpression correlates with poor overall survival (OS). Silencing MICU1 in vitro increases oxygen consumption, decreases lactate production, inhibits clonal growth, migration and invasion of ovarian cancer cells, whereas silencing in vivo inhibits tumour growth, increases cisplatin efficacy and OS. Mechanistically, silencing MICU1 activates pyruvate dehydrogenase (PDH) by stimulating the PDPhosphatase-phosphoPDH-PDH axis. Forced-expression of MICU1 in normal cells phenocopies the metabolic aberrations of malignant cells. Consistent with the in vitro and in vivo findings we observe a significant correlation between MICU1 and pPDH (inactive form of PDH) expression with poor prognosis. Thus, MICU1 could serve as an important therapeutic target to normalize metabolic aberrations responsible for poor prognosis in ovarian cancer.

MicroRNA-144 mediates metabolic shift in ovarian cancer cells by directly targeting Glut1.

Warburg effect is characterized by an increased utilization of glucose via glycolysis in cancer cells, even when enough oxygen is present to properly respire. Recent studies demonstrate that deregulation of microRNAs contributes to the Warburg effect. In the present study, we show that miR-144 is downregulated while glucose transporter 1 (Glut1) is upregulated in ovarian cancers. In vitro studies further showed that miR-144 inhibits Glut1 expression through targeting its 3'-untranslated region. As a result, cells overexpressing miR-144 exhibited a metabolic shift, including enhanced glucose uptake and lactate production. The altered glucose metabolism induced by miR-144 also leads to a rapid growth of ovarian cancer cells. Taken together, our results indicate that miR-144 may serve as a molecular switch to regulate glycolysis in ovarian cancer by targeting the expression of Glut1.

Resveratrol inhibits glucose metabolism in human ovarian cancer cells

Objectives. Resveratrol is a phytoalexin found in grapes that inhibits the in vitro growth of multiple tumor cell types. We showed previously that resveratrol induces autophagic cell death in ovarian cancer cells. Because autophagy is typically an adaptive response to nutrient starvation, we hypothesized that autophagy would also be triggered when ovarian cancer cells are nutrient deprived and that resveratrol could in fact be acting by inducing a starvation-like signaling response. Methods. Ovarian cancer cells were incubated with normal media, media containing resveratrol, glucose free media, or media lacking amino acids. Growth inhibition was determined using the sulforhodamine assay. Cells were evaluated for autophagocytosis by analyzing cleavage of LC3. Glucose uptake, lactate production, and activation of glycolytic regulators pAkt and pmTOR were analyzed following resveratrol treatment. Results. We show here that epithelial ovarian cancer cells are highly sensitive to glucose-deprivation-induced cell death and like resveratrol, glucose deprivation induces caspase-independent cell death with hallmarks of autophagy. Consistent with the hypothesis that resveratrol treatment results in biochemical conditions that mirror a nutrient deprived state, we found that resveratrol dramatically reduces glucose uptake and lactate production. Moreover, resveratrol reduces the levels of phosphorylated Akt and mTOR, two signals that increase glucose uptake and the rate limiting steps in glycolysis. Conclusions. Our findings are consistent with the hypothesis that resveratrol-induced changes in glucose utilization comprise the mechanism that underlies resveratrol-induced autophagocytosis in ovarian cancer. Inhibition of glycolysis in ovarian cancer with resveratrol or other compounds may be effective therapy for ovarian cancer.