scholarly journals Investigation of energy metabolic dynamism in hyperthermia-resistant ovarian and uterine cancer cells under heat stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Taisei Kanamori ◽  
Natumi Miyazaki ◽  
Shigeki Aoki ◽  
Kousei Ito ◽  
Akihiro Hisaka ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Uterine Cancer ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Ubiquitin Pathway ◽  
Atp Production ◽  
Skov3 Cells ◽  
Pathway Analyses ◽  
Rate Limiting ◽  
Glycolytic Rate ◽  
The Warburg Effect

AbstractDespite progress in the use of hyperthermia in clinical practice, the thermosensitivity of cancer cells is poorly understood. In a previous study, we found that sensitivity to hyperthermia varied between ovarian and uterine cancer cell lines. Upon hyperthermia, glycolytic enzymes decreased in hyperthermia-resistant SKOV3 cells. However, the mechanisms of glycolysis inhibition and their relationship with thermoresistance remain to be explored. In this study, metabolomic analysis indicated the downregulation of glycolytic metabolites in SKOV3 cells after hyperthermia. Proteomic and pathway analyses predicted that the ubiquitin pathway was explicitly activated in resistant SKOV3 cells, compared with hyperthermia-sensitive A2780 cells, and STUB1, a ubiquitin ligase, potentially targeted PKM, a glycolytic rate-limiting enzyme. PKM is degraded via ubiquitination upon hyperthermia. Although glycolysis is inactivated by hyperthermia, ATP production is maintained. We observed that oxygen consumption and mitochondrial membrane potential were activated in SKOV3 cells but suppressed in A2780 cells. The activation of mitochondria could compensate for the loss of ATP production due to the suppression of glycolysis by hyperthermia. Although the physiological significance has not yet been elucidated, our results demonstrated that metabolomic adaptation from the Warburg effect to mitochondrial oxidative phosphorylation could contribute to thermoresistance in ovarian and uterine cancer cells.

scholarly journals Ginsenoside 20(S)-Rg3 Inhibits the Warburg Effect Via Modulating DNMT3A/ MiR-532-3p/HK2 Pathway in Ovarian Cancer Cells

2018 ◽  
Vol 45 (6) ◽  
pp. 2548-2559 ◽  
Author(s):  
Yuanyuan Zhou ◽  
Xia Zheng ◽  
Jiaojiao Lu ◽  
Wei Chen ◽  
Xu Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Lactate Production ◽  
Glucose Consumption ◽  
Luciferase Reporter ◽  
Ovarian Cancer Cells ◽  
Skov3 Cells ◽  
Dual Luciferase Reporter Assay ◽  
The Warburg Effect

Background/Aims: The Warburg effect is one of the main energy metabolism features supporting cancer cell growth. 20(S)-Rg3 exerts anti-tumor effect on ovarian cancer partly by inhibiting the Warburg effect. microRNAs are important regulators of the Warburg effect. However, the microRNA regulatory network mediating the anti-Warburg effect of 20(S)-Rg3 was largely unknown. Methods: microRNA deep sequencing was performed to identify the 20(S)-Rg3-influenced microRNAs in SKOV3 ovarian cancer cells. miR-532-3p was overexpressed by mimic532-3p transfection in SKOV3 and A2780 cells or inhibited by inhibitor532-3p transfection in 20(S)-Rg3-treated cells to examine the changes in HK2 and PKM2 expression, glucose consumption, lactate production and cell growth. Dual-luciferase reporter assay was conducted to verify the direct binding of miR-532-3p to HK2. The methylation status in the promoter region of pre-miR-532-3p gene was examined by methylation-specific PCR. Expression changes of key molecules controlling DNA methylation including DNMT1, DNMT3A, DNMT3B, and TET1-3 were examined in 20(S)-Rg3-treated cells. DNMT3A was overexpressed in 20(S)-Rg3-treated cells to examine its influence on miR-532-3p level, HK2 and PKM2 expression, glucose consumption and lactate production. Results: Deep sequencing results showed that 11 microRNAs were increased and 9 microRNAs were decreased by 20(S)-Rg3 in SKOV3 cells, which were verified by qPCR. More than 2-fold increase of miR-532-3p was found in 20(S)-Rg3-treated SKOV3 cells. Forced expression of miR-532-3p reduced HK2 and PKM2 expression, glucose consumption and lactate production in SKOV3 and A2780 ovarian cancer cells. Inhibition of miR-532-3p antagonized the suppressive effect of 20(S)-Rg3 on HK2 and PKM2 expression, glucose consumption and lactate production in ovarian cancer cells. Dual-luciferase reporter assay showed that miR-532-3p directly suppressed HK2 rather than PKM2. miR-532-3p level was controlled by the methylation in the promoter region of its host gene. 20(S)-Rg3 inhibited DNMT3A expression while exerted insignificant effect on DNMT1, DNMT3B and TET1-3. 20(S)-Rg3 reversed DNMT3A-mediated methylation in the promoter of the host gene of miR-532-3p, and thus elevated miR-532-3p level followed by suppression of HK2 and PKM2 expression, glucose consumption and lactate production. Conclusions: 20(S)-Rg3 modulated microRNAs to exert the anti-tumor effect in ovarian cancer. 20(S)-Rg3 lessened the DNMT3A-mediated methylation and promoted the suppression of miR-532-3p on HK2 to antagonize the Warburg effect of ovarian cancer cells.

scholarly journals Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer

2018 ◽  
Vol 18 (6) ◽  
pp. 494-504 ◽  
Author(s):  
Nicholas S. Akins ◽  
Tanner C. Nielson ◽  
Hoang V. Le
Keyword(s):  
Small Molecules ◽  
Cancer Cells ◽  
Pyruvate Kinase ◽  
Energy Demand ◽  
Review Paper ◽  
Chemotherapeutic Agents ◽  
Atp Production ◽  
Enzymatic Mechanism ◽  
Inhibition Of Glycolysis ◽  
The Warburg Effect

Cancer cells have a very different metabolism from that of normal cells from which they are derived. Their metabolism is elevated, which allows them to sustain higher proliferative rate and resist some cell death signals. This phenomenon, known as the “Warburg effect”, has become the focus of intensive efforts in the discovery of new therapeutic targets and new cancer drugs. Both glycolysis and glutaminolysis pathways are enhanced in cancer cells. While glycolysis is enhanced to satisfy the increasing energy demand of cancer cells, glutaminolysis is enhanced to provide biosynthetic precursors for cancer cells. It was recently discovered that there is a tyrosine phosphorylation of a specific isoform of pyruvate kinase, the M2 isoform, that is preferentially expressed in all cancer cells, which results in the generation of pyruvate through a unique enzymatic mechanism that is uncoupled from ATP production. Pyruvate produced through this unique enzymatic mechanism is converted primarily into lactic acid, rather than acetyl-CoA for the synthesis of citrate, which would normally then enter the citric acid cycle. Inhibition of key enzymes in glycolysis and glutaminolysis pathways with small molecules has provided a novel but emerging area of cancer research and has been proven effective in slowing the proliferation of cancer cells, with several inhibitors being in clinical trials. This review paper will cover recent advances in the development of chemotherapeutic agents against several metabolic targets for cancer therapy, including glucose transporters, hexokinase, pyruvate kinase M2, glutaminase, and isocitrate dehydrogenase.

Non-dietary Fructose Metabolism Contributes to the Warburg effect in Cancers

2020 ◽  
Author(s):  
Bing Han ◽  
Lu Wang ◽  
Meilin Wei ◽  
Cynthia Rajani ◽  
Runming Wei ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Glucose Transporter ◽  
Self Control ◽  
Metabolic Reprogramming ◽  
Atp Production ◽  
Fructose Metabolism ◽  
Energy Needs ◽  
Dietary Fructose ◽  
The Warburg Effect

AbstractFructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, dietary fructose rarely enters the bloodstream. Therefore, it remains unclear how cancer cells acquire a sufficient amount of fructose to supplement their energy needs. Here we report that the cancer cells can convert glucose into fructose through intra- and extracellular polyol pathways. The fructose metabolism bypasses normal aerobic respiration’s self-control to supply excessive metabolites to glycolysis and causes the Warburg effect. Inhibition of fructose production drastically suppressed glycolysis and ATP production in cancers. Furthermore, we determined that a glucose transporter, SLC2A8/GLUT8, exports intracellular fructose to other cells in the tumor microenvironment. Taken together, our study identified overlooked fructose resources for cancer cells as an essential part of their metabolic reprogramming and caused the Warburg effect.Statement of SignificanceOur findings in this study suggest that the Warburg effect is actually achieved by means of fructose metabolism, instead of glucose metabolism alone. Fructose metabolism results in accelerated glycolysis and an increased amount of ATP and key intermediates for anabolic metabolism.

scholarly journals Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

2006 ◽  
Vol 175 (6) ◽  
pp. 913-923 ◽  
Author(s):  
Hélène Pelicano ◽  
Rui-hua Xu ◽  
Min Du ◽  
Li Feng ◽  
Ryohei Sasaki ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Mitochondrial Respiration ◽  
Warburg Effect ◽  
Survival Advantage ◽  
Mitochondrial Dna Deletion ◽  
Atp Production ◽  
Akt Activation ◽  
Survival Pathway ◽  
The Warburg Effect

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ-) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents.

scholarly journals A pan-cancer metabolic atlas of the tumor microenvironment

2020 ◽  
Author(s):  
Neha Rohatgi ◽  
Umesh Ghoshdastider ◽  
Probhonjon Baruah ◽  
Anders Jacobsen Skanderup
Keyword(s):  
Cancer Cells ◽  
Stromal Cells ◽  
Metabolic Genes ◽  
Metabolic States ◽  
Tryptophan Catabolism ◽  
Tumor Types ◽  
Rate Limiting ◽  
Pan Cancer ◽  
The Warburg Effect

AbstractTumors are heterogeneous cellular environments with entwined metabolic dependencies. Here, we used a tumor transcriptome deconvolution approach to profile the metabolic states of cancer and non-cancer (stromal) cells in bulk tumors of 20 solid tumor types. We identified metabolic genes and processes recurrently altered in cancer cells across tumor types, including pan-cancer upregulation of deoxythymidine triphosphate (dTTP) production. In contrast, the tryptophan catabolism rate limiting enzymes, IDO1 and TDO2, were highly overexpressed in stroma, suggesting that kynurenine-mediated suppression of antitumor immunity is predominantly constrained by the stroma. Oxidative phosphorylation was unexpectedly the most upregulated metabolic process in cancer cells compared to both stromal cells and a large atlas of cancer cell lines, suggesting that the Warburg effect may be less pronounced in cancer cells in vivo. Overall, our analysis highlights fundamental differences in metabolic states of cancer and stromal cells inside tumors and establishes a pan-cancer resource to interrogate tumor metabolism.

Phytometabolites Targeting the Warburg Effect in Cancer Cells: A Mechanistic Review

2017 ◽  
Vol 18 (9) ◽  
Author(s):  
Mohadeseh Hasanpourghadi ◽  
Chung Yeng Looi ◽  
Ashok Kumar Pandurangan ◽  
Gautam Sethi ◽  
Won Fen Wong ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
The Warburg Effect

Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect

2018 ◽  
Vol 1870 (1) ◽  
pp. 51-66 ◽  
Author(s):  
Linchong Sun ◽  
Caixia Suo ◽  
Shi-ting Li ◽  
Huafeng Zhang ◽  
Ping Gao
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Metabolic Reprogramming ◽  
The Warburg Effect

Selective killing of cancer cells by leaf extract of Ashwagandha: Components, activity and pathway analyses

2008 ◽  
Vol 262 (1) ◽  
pp. 37-47 ◽  
Author(s):  
Nashi Widodo ◽  
Yasuomi Takagi ◽  
Bhupal G. Shrestha ◽  
Tetsuro Ishii ◽  
Sunil C. Kaul ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Leaf Extract ◽  
Pathway Analyses

scholarly journals Dasatinib (BMS-35482) Interacts Synergistically With Docetaxel, Gemcitabine, Topotecan, and Doxorubicin in Ovarian Cancer Cells With High SRC Pathway Activation and Protein Expression

2014 ◽  
Vol 24 (2) ◽  
pp. 218-225 ◽  
Author(s):  
Angeles Alvarez Secord ◽  
Deanna Teoh ◽  
Jingquan Jia ◽  
Andrew B. Nixon ◽  
Lisa Grace ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Protein Expression ◽  
Cancer Cells ◽  
Combination Index ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Ovarian Cancer Cells ◽  
Response Curves ◽  
Pathway Activation ◽  
Skov3 Cells

PurposeThis study aimed to explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells.MethodsCells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pretreatment and posttreatment. Dose-response curves were constructed, and the combination index (CI) for drug interaction was calculated.ResultsIn the IGROV1 cells, dasatinib alone reduced phospho-SRC/total SRC 71% and p-paxillin/t-paxillin ratios 77%. Phospho-SRC (3%–33%; P = 0.002 to 0.04) and p-paxicillin (6%–19%; P = 0.01 to 0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine, or topotecan had a synergistic antiproliferative effect (CI, 0.49–0.68), whereas dasatinib combined with doxorubicin had an additive effect (CI, 1.08).In SKOV3 cells, dasatinib resulted in less pronounced reductions of phospho-SRC/total SRC (49%) and p-paxillin/t-paxillin (62%). Phospho-SRC (18%; P < 0.001) and p-paxillin levels (18%; P = 0.001; 9%; P = 0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on the proliferation of these cells (CI, 1.49–2.27).ConclusionsDasatinib in combination with relapse chemotherapeutic agents seems to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy are warranted.

scholarly journals TAMI-35. AUTOPHAGY MEDIATED LIPID CATABOLISM FACILITATES GLIOMA PROGRESSION TO OVERCOME BIOENERGETIC CRISIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii220-ii220
Author(s):  
Chenran Wang ◽  
Michael Haas ◽  
Syn Yeo ◽  
Ritama Paul ◽  
Fuchun Yang ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Cancer Cells ◽  
Strong Association ◽  
Glioma Cells ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Atp Production ◽  
Lipid Catabolism ◽  
Mtorc1 Signaling

Abstract Activation of mTORC1 plays a significant role in cancer development and progression. However, the metabolic mechanisms to sustain mTORC1 activation in stressed cancer cells are still underappreciated. Autophagy, one downstream process of mTORC1, is proposed to be suppressed under the condition of mTORC1 hyper-activation. Interestingly, we recently revealed higher autophagy activity in various Tsc-deficient tumor cells with mTORC1 hyper-activity. Nevertheless, the functions and mechanisms of autophagy in regulating mTORC1 in cancer cells are not well understood. In this study, we revealed a strong association of altered mRNA levels in mTORC1 upstream and downstream genes with poor prognosis of glioma patients. Our metabolic and molecular studies indicated that autophagy mediated lipid catabolism was essential to sustain mTORC1 activity in glioma cells under energy stresses. We found that autophagy inhibitors or fatty acid oxidation (FAO) inhibition in combination with 2-Deoxy-D-glucose (2DG) decreased oxidative phosphorylation, ATP production, mTORC1 activity, and survival of glioma cells in vitro. Consistently, the combination of chloroquine (CQ) or FAO inhibitors with 2DG effectively suppressed the progression of xenografted glioma with mTORC1 hyperactivation in mice. This study established a novel autophagy/lipid degradation/FAO/ATP pathway that maintains high mTORC1 signaling and tumor progression in brain cancer cells under energy stresses. The requirement of lipophagy in brain cancers may provide an opportunity to develop new molecular therapeutic targets to counteract mTORC1 for tumor progression.

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