scholarly journals SPARC Inhibits Metabolic Plasticity in Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 385 ◽  
Author(s):  
Christine Naczki ◽  
Bincy John ◽  
Chirayu Patel ◽  
Ashlyn Lafferty ◽  
Alia Ghoneum ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Redox Homeostasis ◽  
Tca Cycle ◽  
High Energy ◽  
Inhibitory Effect ◽  
Tumor Burden ◽  
Ros Generation ◽  
Atp Production ◽  
Metabolic Plasticity

The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic cascades, but also in the modulation of cancer cell metabolic plasticity to fulfill their high energy demands. In this respect, we investigated the role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in metabolic plasticity of OvCa. We used a syngeneic model of OvCa in Sparc-deficient and proficient mice to gain comprehensive insight into the paracrine effect of stromal-SPARC in metabolic programming of OvCa in the peritoneal milieu. Metabolomic and transcriptomic profiling of micro-dissected syngeneic peritoneal tumors revealed that the absence of stromal-Sparc led to significant upregulation of the enzymes involved in glycolysis, TCA cycle, and mitochondrial electron transport chain (ETC), and their metabolic intermediates. Absence of stromal-Sparc increased reactive oxygen species and perturbed redox homeostasis. Recombinant SPARC exerted a dose-dependent inhibitory effect on glycolysis, mitochondrial respiration, ATP production and ROS generation. Comparative analysis with human tumors revealed that SPARC-regulated ETC-signature inversely correlated with SPARC transcripts. Targeting mitochondrial ETC by phenformin treatment of tumor-bearing Sparc-deficient and proficient mice mitigated the effect of SPARC-deficiency and significantly reduced tumor burden, ROS, and oxidative tissue damage in syngeneic tumors. In summary, our findings provide novel insights into the role of SPARC in regulating metabolic plasticity and bioenergetics in OvCa, and shines light on its potential therapeutic efficacy.

scholarly journals The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770550 ◽  
Author(s):  
Yi Li ◽  
Ming Xiao ◽  
Fangchun Guo
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Conditioned Medium ◽  
Umbilical Vein ◽  
Inhibitory Effect ◽  
Ovarian Cancer Cells ◽  
Human Umbilical Vein ◽  
Tumor Tissues

SOX6 plays important roles in cell proliferation, differentiation, and cell fate determination. It has been confirmed that SOX6 is a tumor suppressor and downregulated in various cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and chronic myeloid leukemia. Netrin-1 is highly expressed in various human cancers and acts as an anti-apoptotic and proangiogenic factor to drive tumorigenesis. The role of SOX6 and netrin-1 in regulating the growth of ovarian tumor cells still remains unclear. Real-time polymerase chain reaction and western blot were used to determine the SOX6 messenger RNA and protein levels, respectively, in ovarian cancer cells and tumor tissues. Stable transfection of SOX6 was conducted to overexpress SOX6 in PA-1 and SW626 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Invasion of ovarian cancer cells and migration of human umbilical vein endothelial cells were confirmed by Transwell assays. To overexpress netrin-1, ovarian cancer cells with SOX6 restoration was transduced with netrin-1 lentiviral particles. PA-1 xenografts in a nude mice model were used to conduct in vivo evaluation of the role of SOX6 and its relationship with netrin-1 in tumor growth and angiogenesis. In this study, we found significantly reduced SOX6 levels in PA-1, SW626, SK-OV-3, and CaoV-3 ovarian cancer cell lines and human tumor tissues in comparison with normal human ovarian epithelial cells or matched non-tumor tissues. SOX6 overexpression by stable transfection dramatically inhibited proliferation and invasion of PA-1 and SW626 cells. Also, conditioned medium from PA-1 and SW626 cells with SOX6 restoration exhibited reduced ability to induce human umbilical vein endothelial cells migration and tube formation compared with conditioned medium from the cells with transfection control. Furthermore, an inverse relationship between SOX6 and netrin-1 expression was observed in PA-1 and SW626 cells. Overexpression of netrin-1 in ovarian cancer cells with forced SOX6 expression remarkably abrogated the inhibitory effect of SOX6 on proliferation, invasion of the cells, and tumor xenograft growth and vascularity in vivo. Human umbilical vein endothelial cell migration and tube formation were enhanced in the conditioned medium from the ovarian cancer cells transduced with netrin-1 lentivirus particles. Our observations revealed that SOX6 is a tumor suppressor in ovarian cancer cells, and SOX6 exerts an inhibitory effect on the proliferation, invasion, and tumor cell-induced angiogenesis of ovarian cancer cells, whereas nerin-1 plays an opposite role and its expression is inversely correlated with SOX6. Moreover, our findings suggest a new role of SOX6 and netrin-1 for understanding the progression of ovarian cancer and have the potential for the development of new diagnosis and treatment strategies for ovarian cancer.

Connexin 43 Knockdown Induces Mitochondrial Dysfunction and Affects Early Developmental Competence in Porcine Embryos

2020 ◽  
Vol 26 (2) ◽  
pp. 287-296
Author(s):  
Kyung-Tae Shin ◽  
Zheng-Wen Nie ◽  
Wenjun Zhou ◽  
Dongjie Zhou ◽  
Ju-Yeon Kim ◽  
...  
Keyword(s):  
Membrane Permeability ◽  
Connexin 43 ◽  
Molecular Mechanisms ◽  
Developmental Competence ◽  
Cell Junction ◽  
Ros Generation ◽  
Blastocyst Development ◽  
Atp Production ◽  
Early Embryos

AbstractConnexin 43 (CX43) is a component of gap junctions. The lack of functional CX43 induces oxidative stress, autophagy, and apoptosis in somatic cells. However, the role of CX43 in the early development of porcine embryos is still unknown. Thus, the aim of this study was to investigate the role of CX43, and its underlying molecular mechanisms, on the developmental competence of early porcine embryos. We performed CX43 knockdown by microinjecting dsRNA into parthenogenetically activated porcine parthenotes. The blastocyst development rate and the total number of cells in the blastocysts were significantly reduced by CX43 knockdown. Results from FITC-dextran assays showed that CX43 knockdown significantly increased membrane permeability. ZO-1 protein was obliterated in CX43 knockdown blastocysts. Mitochondrial membrane potential and ATP production were significantly reduced following CX43 knockdown. Reactive oxygen species (ROS) levels were significantly increased in the CX43 knockdown group compared to those in control embryos. Moreover, CX43 knockdown induced autophagy and apoptosis. Our findings indicate that CX43 is essential for the development and preimplantation of porcine embryos and maintains mitochondrial function, cell junction structure, and cell homeostasis by regulating membrane permeability, ROS generation, autophagy, and apoptosis in early embryos.

scholarly journals Novel role of lncRNA CHRF in cisplatin resistance of ovarian cancer is mediated by miR-10b induced EMT and STAT3 signaling

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wen-Xi Tan ◽  
Ge Sun ◽  
Meng-Yuan Shangguan ◽  
Zhi Gui ◽  
Yang Bao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cisplatin Resistance ◽  
Gynecological Cancer ◽  
Acquired Resistance ◽  
Tumor Burden ◽  
Human Patient ◽  
Mesenchymal Transition ◽  
Stat3 Signaling

Abstract Ovarian Cancer (OC) is a highly lethal gynecological cancer which often progresses through acquired resistance against the administered therapy. Cisplatin is a common therapeutic for the treatment of OC patients and therefore it is critical to understand the mechanisms of resistance against this drug. We studied a paired cell line consisting of parental and cisplatin resistant (CR) derivative ES2 OC cells, and found a number of dysregulated lncRNAs, with CHRF being the most significantly upregulated lncRNA in CR ES2 cells. The findings corroborated in human patient samples and CHRF was significantly elevated in OC patients with resistant disease. CHRF was also found to be elevated in patients with liver metastasis. miR-10b was found to be mechanistically involved in CHRF mediated cisplatin resistance. It induced resistance in not only ES2 but also OVCAR and SKOV3 OC cells. Induction of epithelial-to-mesenchymal-transition (EMT) and activation of STAT3 signaling were determined to be the mechanisms underlying the CHRF-miR-10b axis-mediated cisplatin resistance. Down-regulation of CHRF reversed EMT, STAT3 activation and the resulting cisplatin resistance, which could be attenuated by miR-10b. The results were also validated in an in vivo cisplatin resistance model wherein CR cells were associated with increased tumor burden, CHRF downregulation associated with decreased tumor burden and miR-10b again attenuated the CHRF downregulation effects. Our results support a novel role of lncRNA CHRF in cisplatin resistance of OC and establish CHRF-miR-10b signaling as a putative therapeutic target for sensitizing resistant OC cells.

scholarly journals Catalase deficiency facilitates the shuttling of free fatty acid to brown adipose tissue through lipolysis mediated by ROS during sustained fasting

2021 ◽  
Author(s):  
Raghbendra Kumar Dutta ◽  
Joon No Lee ◽  
Yunash Maharjan ◽  
Channy Park ◽  
Seong-Kyu Choe ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Brown Adipose Tissue ◽  
Energy Homeostasis ◽  
Redox Homeostasis ◽  
Ros Generation ◽  
Peroxisomal Enzyme ◽  
Triglyceride Accumulation ◽  
Brown Adipose

Abstract Background Fatty acids (FA) derived from adipose tissue and liver serve as the main fuel in thermogenesis of brown adipose tissue (BAT). Catalase, a peroxisomal enzyme, plays an important role in maintaining intracellular redox homeostasis by decomposing hydrogen peroxide to either water or oxygen that oxidize and provide fuel for cellular metabolism. Although the antioxidant enzymatic activity of catalase is well known, its role in the metabolism and maintenance of energy homeostasis has not yet been revealed. The present study investigated the role of catalase in lipid metabolism and thermogenesis during nutrient deprivation in catalase-knockout (KO) mice. Results We found that hepatic triglyceride accumulation in KO mice decreased during sustained fasting due to lipolysis through reactive oxygen species (ROS) generation in adipocytes. Furthermore, the free FA released from lipolysis were shuttled to BAT through the activation of CD36 and catabolized by lipoprotein lipase in KO mice during sustained fasting. Although the exact mechanism for the activation of the FA receptor enzyme is still unclear, we found that ROS generation in adipocytes mediated the shuttling of FA to BAT. Conclusions Taken together, our findings uncover the novel role of catalase in lipid metabolism and thermogenesis in BAT, which may be useful in understanding metabolic dysfunction.

scholarly journals Metabolic Plasticity of Acute Myeloid Leukemia

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 805 ◽  
Author(s):  
Johanna Kreitz ◽  
Christine Schönfeld ◽  
Marcel Seibert ◽  
Verena Stolp ◽  
Islam Alshamleh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Environmental Changes ◽  
Redox Homeostasis ◽  
Tca Cycle ◽  
Building Blocks ◽  
Continuous Growth ◽  
Metabolic Plasticity ◽  
Life Threatening ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is one of the most common and life-threatening leukemias. A highly diverse and flexible metabolism contributes to the aggressiveness of the disease that is still difficult to treat. By using different sources of nutrients for energy and biomass supply, AML cells gain metabolic plasticity and rapidly outcompete normal hematopoietic cells. This review aims to decipher the diverse metabolic strategies and the underlying oncogenic and environmental changes that sustain continuous growth, mediate redox homeostasis and induce drug resistance in AML. We revisit Warburg’s hypothesis and illustrate the role of glucose as a provider of cellular building blocks rather than as a supplier of the tricarboxylic acid (TCA) cycle for energy production. We discuss how the diversity of fuels for the TCA cycle, including glutamine and fatty acids, contributes to the metabolic plasticity of the disease and highlight the roles of amino acids and lipids in AML metabolism. Furthermore, we point out the potential of the different metabolic effectors to be used as novel therapeutic targets.

Ca2+ activation of heart mitochondrial oxidative phosphorylation: role of the F0/F1-ATPase

2000 ◽  
Vol 278 (2) ◽  
pp. C423-C435 ◽  
Author(s):  
Paul R. Territo ◽  
Vamsi K. Mootha ◽  
Stephanie A. French ◽  
Robert S. Balaban
Keyword(s):  
Oxidative Phosphorylation ◽  
Atp Synthesis ◽  
High Energy ◽  
Ruthenium Red ◽  
Maximal Effect ◽  
Production Rates ◽  
Atp Production ◽  
The Matrix

Ca2+ has been postulated as a cytosolic second messenger in the regulation of cardiac oxidative phosphorylation. This hypothesis draws support from the well-known effects of Ca2+ on muscle activity, which is stimulated in parallel with the Ca2+-sensitive dehydrogenases (CaDH). The effects of Ca2+ on oxidative phosphorylation were further investigated in isolated porcine heart mitochondria at the level of metabolic driving force (NADH or Δψ) and ATP production rates (flow). The resulting force-flow (F-F) relationships permitted the analysis of Ca2+ effects on several putative control points within oxidative phosphorylation, simultaneously. The F-F relationships resulting from additions of carbon substrates alone provided a model of pure CaDH activation. Comparing this curve with variable Ca2+ concentration ([Ca2+]) effects revealed an approximate twofold higher ATP production rate than could be explained by a simple increase in NADH or Δψ via CaDH activation. The half-maximal effect of Ca2+ at state 3 was 157 nM and was completely inhibited by ruthenium red (1 μM), indicating matrix dependence of the Ca2+ effect. Arsenate was used as a probe to differentiate between F0/F1-ATPase and adenylate translocase activity by a futile recycling of ADP-arsenate within the matrix, catalyzed by the F0/F1-ATPase. Ca2+increased the ADP arsenylation rate more than twofold, suggesting a direct effect on the F0/F1-ATPase. These results suggest that Ca2+ activates cardiac aerobic respiration at the level of both the CaDH and F0/F1-ATPase. This type of parallel control of both intermediary metabolism and ATP synthesis may provide a mechanism of altering ATP production rates with minimal changes in the high-energy intermediates as observed in vivo.

scholarly journals Slow TCA flux implies low ATP production in tumors

2021 ◽  
Author(s):  
Caroline R. Bartman ◽  
Yihui Shen ◽  
Won Dong Lee ◽  
Tara TeSlaa ◽  
Connor S.R. Jankowski ◽  
...  
Keyword(s):  
Electron Transport ◽  
Warburg Effect ◽  
Electron Transport Chain ◽  
Aerobic Glycolysis ◽  
Tca Cycle ◽  
High Energy ◽  
Glycolytic Flux ◽  
Atp Production ◽  
Transport Chain ◽  
The Warburg Effect

SummaryThe tricarboxylic acid (TCA) cycle oxidizes carbon substrates to carbon dioxide, with the resulting high energy electrons fed into the electron transport chain to produce ATP by oxidative phosphorylation. Healthy tissues derive most of their ATP from oxidative metabolism, and the remainder from glycolysis. The corresponding balance in tumors remains unclear. Tumors upregulate aerobic glycolysis (the Warburg effect), yet they also typically require an intact TCA cycle and electron transport chain1–6. Recent studies have measured which nutrients contribute carbon to the tumor TCA metabolites7,8, but not tumor TCA flux: how fast the cycle turns. Here, we develop and validate an in vivo dynamic isotope tracing-mass spectrometry strategy for TCA flux quantitation, which we apply to all major mouse organs and to five tumor models. We show that, compared to the tissue of origin, tumor TCA flux is markedly suppressed. Complementary glycolytic flux measurements confirm tumor glycolysis acceleration, but the majority of tumor ATP is nevertheless made aerobically, and total tumor ATP production is suppressed compared to healthy tissues. In murine pancreatic cancer, this is accommodated by downregulation of the major energy-using pathway in the healthy exocrine pancreas, protein synthesis. Thus, instead of being hypermetabolic as commonly assumed, tumors apparently make ATP at a lower than normal rate. We propose that, as cells de-differentiate into cancer, they eschew ATP-intensive processes characteristic of the host tissue, and that the resulting suppressed ATP demand contributes to the Warburg effect and facilitates cancer growth in the nutrient-poor tumor microenvironment.

scholarly journals Extracellular Matrix Signals as Drivers of Mitochondrial Bioenergetics and Metabolic Plasticity of Cancer Cells During Metastasis

2021 ◽  
Vol 9 ◽  
Author(s):  
Félix A. Urra ◽  
Sebastián Fuentes-Retamal ◽  
Charlotte Palominos ◽  
Yarcely A. Rodríguez-Lucart ◽  
Camila López-Torres ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Rho Gtpases ◽  
Therapeutic Potential ◽  
Mitochondrial Metabolism ◽  
Migration And Invasion ◽  
Mitochondrial Bioenergetics ◽  
Atp Production ◽  
Metabolic Plasticity

The role of metabolism in tumor growth and chemoresistance has received considerable attention, however, the contribution of mitochondrial bioenergetics in migration, invasion, and metastasis is recently being understood. Migrating cancer cells adapt their energy needs to fluctuating changes in the microenvironment, exhibiting high metabolic plasticity. This occurs due to dynamic changes in the contributions of metabolic pathways to promote localized ATP production in lamellipodia and control signaling mediated by mitochondrial reactive oxygen species. Recent evidence has shown that metabolic shifts toward a mitochondrial metabolism based on the reductive carboxylation, glutaminolysis, and phosphocreatine-creatine kinase pathways promote resistance to anoikis, migration, and invasion in cancer cells. The PGC1a-driven metabolic adaptations with increased electron transport chain activity and superoxide levels are essential for metastasis in several cancer models. Notably, these metabolic changes can be determined by the composition and density of the extracellular matrix (ECM). ECM stiffness, integrins, and small Rho GTPases promote mitochondrial fragmentation, mitochondrial localization in focal adhesion complexes, and metabolic plasticity, supporting enhanced migration and metastasis. Here, we discuss the role of ECM in regulating mitochondrial metabolism during migration and metastasis, highlighting the therapeutic potential of compounds affecting mitochondrial function and selectively block cancer cell migration.

Inhibitory Effect of the Zinc Metallochaperone NSC319726 on Ovarian Cancer Cells via the Regulation of P53

2021 ◽  
Author(s):  
Shikui Sun ◽  
Yue Liang ◽  
Ke Li ◽  
Yizhen Wang ◽  
Huimin Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Suppressor Gene ◽  
Inhibitory Effect ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Cyclin Dependent Kinase ◽  
Tumor Protein P53 ◽  
Novel Drug

Abstract Ovarian cancer is the leading cause of death from malignancies of the female reproductive system. In recent years, there has been little development regarding the treatment of ovarian cancer. Wild-type tumor protein p53 (P53) can inhibit the development of tumor, however, mutations in P53 have been shown in most cases of ovarian cancer. The mutated gene encoded P53 transforms from a tumor suppressor gene to an oncogene, losing its original anti-tumor function. Studies have shown that the zinc metallochaperone NSC319726 can promote the correct folding of P53 in cancer cells and restore its physiological function, however, the function of NSC319726 in ovarian cancer has not been elaborated. So we investigated the role of NSC319726 on biological functions of ovarian cancer and preliminarily determined the specific molecular mechanism. The results showed that NSC319726 could inhibit proliferation, migration and invasion of ovarian cancer cells and promote their apoptosis. Mechanically, NSC319726 regains the tumor-suppressed function of P53, further activates the downstream cyclin-dependent kinase CDK inhibited protein P21, thereby blocking the cell cycle and inhibiting cells proliferation. Therefore, NSC319726 has the potential to act as a novel drug for treating ovarian cancer.

Sign in / Sign up

Export Citation Format

Share Document