scholarly journals Warburg Effect Is a Cancer Immune Evasion Mechanism Against Macrophage Immunosurveillance

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing Chen ◽  
Xu Cao ◽  
Bolei Li ◽  
Zhangchen Zhao ◽  
Siqi Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Evasion ◽  
Warburg Effect ◽  
Therapeutic Potential ◽  
Tumor Development ◽  
Extracellular Acidification ◽  
Extracellular Medium ◽  
The Warburg Effect

Evasion of immunosurveillance is critical for cancer initiation and development. The expression of “don’t eat me” signals protects cancer cells from being phagocytosed by macrophages, and the blockade of such signals demonstrates therapeutic potential by restoring the susceptibility of cancer cells to macrophage-mediated phagocytosis. However, whether additional self-protective mechanisms play a role against macrophage surveillance remains unexplored. Here, we derived a macrophage-resistant cancer model from cells deficient in the expression of CD47, a major “don’t eat me” signal, via a macrophage selection assay. Comparative studies performed between the parental and resistant cells identified self-protective traits independent of CD47, which were examined with both pharmacological or genetic approaches in in vitro phagocytosis assays and in vivo tumor models for their roles in protecting against macrophage surveillance. Here we demonstrated that extracellular acidification resulting from glycolysis in cancer cells protected them against macrophage-mediated phagocytosis. The acidic tumor microenvironment resulted in direct inhibition of macrophage phagocytic ability and recruitment of weakly phagocytic macrophages. Targeting V-ATPase which transports excessive protons in cancer cells to acidify extracellular medium elicited a pro-phagocytic microenvironment with an increased ratio of M1-/M2-like macrophage populations, therefore inhibiting tumor development and metastasis. In addition, blockade of extracellular acidification enhanced cell surface exposure of CD71, targeting which by antibodies promoted cancer cell phagocytosis. Our results reveal that extracellular acidification due to the Warburg effect confers immune evasion ability on cancer cells. This previously unrecognized role highlights the components mediating the Warburg effect as potential targets for new immunotherapy harnessing the tumoricidal capabilities of macrophages.

scholarly journals LncRNA OIP5-AS1 Regulates the Warburg Effect Through miR-124-5p/IDH2/HIF-1α Pathway in Cervical Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Li Li ◽  
Yan Ma ◽  
Kamalibaike Maerkeya ◽  
Davuti Reyanguly ◽  
Lili Han
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Warburg Effect ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
Cervical Cancer Cells ◽  
The Warburg Effect

Hypoxia reprogrammed glucose metabolism affects the Warburg effect of tumor cells, but the mechanism is still unclear. Long-chain non-coding RNA (lncRNA) has been found by many studies to be involved in the Warburg effect of tumor cells under hypoxic condition. Herein, we find that lncRNA OIP5-AS1 is up-regulated in cervical cancer tissues and predicts poor 5-years overall survival in cervical cancer patients, and it promotes cell proliferation of cervical cancer cells in vitro and in vivo. Moreover, OIP5-AS1 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis which is IDH2 or hypoxia inducible factor-1α (HIF-1α) dependent. In cervical cancer cells, OIP5-AS1 promotes IDH2 expression by inhibiting miR-124-5p, and IDH2 promotes the Warburg effect of cervical under hypoxic condition through regulating HIF-1α expression. In conclusion, hypoxia induced OIP5-AS1 promotes the Warburg effect through miR-124-5p/IDH2/HIF-1α pathway in cervical cancer.

In vitro and in vivo investigations of novel 1,4-napthoquinone sulphomethylene carbohydrate conjugates in prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 104-104
Author(s):  
Tobias Busenbender ◽  
Sergey Dyshlovoy ◽  
Moritz Kaune ◽  
Lukas Boeckelmann ◽  
Tobias Lange ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Apoptotic Pathway ◽  
The Warburg Effect

104 Background: The Warburg effect describes the ability of cancer cells to consume larger amounts of glucose in comparison to normal tissue, due to the overexpression of insulin-independent glucose transporters (e.g. GLUT1). This effect can be used to enhance the selectivity and reduce side effects of cytotoxic anticancer molecules by its conjugation to sugar residues, thus, generating cytotoxic agents showing higher selectivity to cancer cells. In continuation of our research on anticancer natural 1,4-naphthoquinones we have investigated a large series of novel semi-synthetic molecules containing 1,4-naphthoquinones element conjugated with glucose molecule via -S-CH2- bond. Methods: We performed screening examinations for 35 novel synthetic molecules in human prostate cancer in vitro. The selected most active compounds were tested in several human prostate cancer cell lines harboring different levels of drug resistance, as well as in non-malignant cells to specify their selectivity. Compounds with the highest cytotoxicity and selectivity were further investigated. The mode of action was assessed including effects on apoptosis induction, oxidative stress, mitochondria, AR-signaling as well as glucose uptake and ER stress were assessed. In vivo dose finding and efficacy analyses were performed. Results: We identified two promising derivatives, showing IC50s at low micro- and nanomolar concentrations. Glucose depletion from the culture media led to increased cytotoxicity and cotreatment with a GLUT1-inhibitor showed an antagonistic effect, suggesting a concurrent uptake and therefore a Warburg effect targeting. The selected compounds exhibited most pronounced cytotoxic activity in DU145 cells as well as 22Rv1 cells. Non-malignant cells were generally less affected. The mode of action involves a loss of mitochondrial membrane potential, a release of cytochrome c and AIF into the cytosol and an upregulation of caspase-9, caspase-3 and cleaved PARP, as well as downregulation of Bcl-2 and Survivin, indicating that mitochondria are a major target, leading to the activation of the intrinsic apoptotic pathway. Early events in treated cells are ROS production and calcium release into the cytosol, a marker of ER-stress. Furthermore, downregulation of the AR and its signaling was observed on mRNA- and protein-level. In vivo experiments revealed antitumor activity in a 22Rv1-xenograft mouse model without severe side effects. Conclusions: In conclusion, we were able to identify two glucose-conjugated 1,4-naphthoquinones exhibiting potent in vitro and in vivoactivity and selectivity in human prostate cancer cells due to the Warburg effect targeting. Cytotoxic activity was exerted via initial ROS production and ER stress leading to mitochondrial damage and the induction of the intrinsic apoptotic pathway.

scholarly journals Proton export drives the Warburg Effect

2021 ◽  
Author(s):  
Shonagh Russell ◽  
Liping Xu ◽  
Yoonseok Kam ◽  
Dominique Abrahams ◽  
Bryce Ordway ◽  
...  
Keyword(s):  
Warburg Effect ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Glycolytic Enzymes ◽  
Hek293 Cells ◽  
Driver Mutations ◽  
The Warburg Effect

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect”. It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.

scholarly journals The Functional Implications of Endothelial Gap Junctions and Cellular Mechanics in Vascular Angiogenesis

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 237 ◽  
Author(s):  
Takayuki Okamoto ◽  
Haruki Usuda ◽  
Tetsuya Tanaka ◽  
Koichiro Wada ◽  
Motomu Shimaoka
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Gap Junctions ◽  
Gap Junction ◽  
Cancer Cells ◽  
Tumor Development ◽  
Tube Formation ◽  
Cellular Mechanics

Angiogenesis—the sprouting and growth of new blood vessels from the existing vasculature—is an important contributor to tumor development, since it facilitates the supply of oxygen and nutrients to cancer cells. Endothelial cells are critically affected during the angiogenic process as their proliferation, motility, and morphology are modulated by pro-angiogenic and environmental factors associated with tumor tissues and cancer cells. Recent in vivo and in vitro studies have revealed that the gap junctions of endothelial cells also participate in the promotion of angiogenesis. Pro-angiogenic factors modulate gap junction function and connexin expression in endothelial cells, whereas endothelial connexins are involved in angiogenic tube formation and in the cell migration of endothelial cells. Several mechanisms, including gap junction function-dependent or -independent pathways, have been proposed. In particular, connexins might have the potential to regulate cell mechanics such as cell morphology, cell migration, and cellular stiffness that are dynamically changed during the angiogenic processes. Here, we review the implication for endothelial gap junctions and cellular mechanics in vascular angiogenesis.

scholarly journals PHF14 Promotes Cell Proliferation and Migration through the AKT and ERK1/2 Pathways in Gastric Cancer Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Yuzu Zhao ◽  
Jiang He ◽  
Yongsen Li ◽  
Man Xu ◽  
Xingzhi Peng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Tumor Development ◽  
Tumor Promoter ◽  
Clinical Samples ◽  
Gastric Cancer Cells ◽  
Phosphorylated Akt

PHF14 is a new member belonging to PHD finger proteins. PHF14 is involved in multiple biologic processes including Dandy–Walker syndrome, mesenchyme growth, lung fibrosis, renal fibrosis, persistent pulmonary hypertension, and tumor development. This study aims to explore whether PHF14 plays an important role in gastric cancer. Here, PHF14 is indicated as a tumor promoter. The expression of PHF14 enhances no matter in clinical samples or in gastric cancer cells. High expression of PHF14 impairs survival of patients. Attenuation of PHF14 inhibits cell proliferation in gastric cancer cells. PHF14 downregulation inhibits the expression of cell cycle-related proteins, CDK6 and cyclin D1. Furthermore, silencing of PHF14 reduces the level of phosphorylated AKT as well as phosphorylated ERK1/2. Finally, downregulation of PHF14 in gastric cancer cells inhibits colony formation in vitro and tumorigenesis in vivo. These results indicate that PHF14 promotes tumor development in gastric cancer, so PHF14 thereby acts as a potential target for gastric cancer therapy.

scholarly journals miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Shihua Wu ◽  
Feng Liu ◽  
Liming Xie ◽  
Yaling Peng ◽  
Xiaoyuan Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Clinical Stage ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Progression

Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR-125b elicits these responses by directly targeting MCL1 (myeloid cell leukemia 1), which results in a marked reduction in MCL1 expression. Transfection of miR-125b sensitizes gastric cancer cells to 5-FU-induced apoptosis. By understanding the function and molecular mechanisms of miR-125b in gastric cancer, we may learn that miR-125b has the therapeutic potential to suppress gastric cancer progression and increase drug sensitivity to gastric cancer.

scholarly journals Five-Decade Update on Chemopreventive and Other Pharmacological Potential of Kurarinone: a Natural Flavanone

2021 ◽  
Vol 12 ◽  
Author(s):  
Shashank Kumar ◽  
Kumari Sunita Prajapati ◽  
Mohd Shuaib ◽  
Prem Prakash Kushwaha ◽  
Hardeep Singh Tuli ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Experimental Models ◽  
Xenograft Models ◽  
Inhibitory Potential ◽  
Pharmacological Potential

In the present article we present an update on the role of chemoprevention and other pharmacological activities reported on kurarinone, a natural flavanone (from 1970 to 2021). To the best of our knowledge this is the first and exhaustive review of kurarinone. The literature was obtained from different search engine platforms including PubMed. Kurarinone possesses anticancer potential against cervical, lung (non-small and small), hepatic, esophageal, breast, gastric, cervical, and prostate cancer cells. In vivo anticancer potential of kurarinone has been extensively studied in lungs (non-small and small) using experimental xenograft models. In in vitro anticancer studies, kurarinone showed IC50 in the range of 2–62 µM while in vivo efficacy was studied in the range of 20–500 mg/kg body weight of the experimental organism. The phytochemical showed higher selectivity toward cancer cells in comparison to respective normal cells. kurarinone inhibits cell cycle progression in G2/M and Sub-G1 phase in a cancer-specific context. It induces apoptosis in cancer cells by modulating molecular players involved in apoptosis/anti-apoptotic processes such as NF-κB, caspase 3/8/9/12, Bcl2, Bcl-XL, etc. The phytochemical inhibits metastasis in cancer cells by modulating the protein expression of Vimentin, N-cadherin, E-cadherin, MMP2, MMP3, and MMP9. It produces a cytostatic effect by modulating p21, p27, Cyclin D1, and Cyclin A proteins in cancer cells. Kurarinone possesses stress-mediated anticancer activity and modulates STAT3 and Akt pathways. Besides, the literature showed that kurarinone possesses anti-inflammatory, anti-drug resistance, anti-microbial (fungal, yeast, bacteria, and Coronavirus), channel and transporter modulation, neuroprotection, and estrogenic activities as well as tyrosinase/diacylglycerol acyltransferase/glucosidase/aldose reductase/human carboxylesterases 2 inhibitory potential. Kurarinone also showed therapeutic potential in the clinical study. Further, we also discussed the isolation, bioavailability, metabolism, and toxicity of Kurarinone in experimental models.

The use of L-glucose in cancer diagnosis: Results from In Vitro and In Vivo Studies

2021 ◽  
Vol 28 ◽  
Author(s):  
Ioanna A. Anastasiou ◽  
Ioanna Eleftheriadou ◽  
Anastasios Tentolouris ◽  
Iordanis Mourouzis ◽  
Constantinos Pantos ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Diagnosis ◽  
English Language ◽  
Research Work ◽  
Tumor Development ◽  
Mirror Image ◽  
In Vivo Studies ◽  
Cochrane Library

Background:: Cancer cells are characterized by metabolic heterogeneity. Although many research groups make efforts to analyze this heterogeneity, little attention has been paid to the scenario that cancer cells may utilize otherwise unusable substrates as fuel for tumor development. Of the two stereoisomers of glucose, D-glucose but not L-glucose, the mirror image isomer of D-glucose, is abundantly found in nature. D-glucose is the human body's key source of energy, through aerobic respiration. However, data from in vitro and in vivo studies examining the ability of cancer cells to take up L-glucose are scarce. Objectives: The present mini-review aims to present current literature data on the role of L-glucose in cancer diagnosis based on in vitro and in vivo studies. Methods: The MEDLINE, EMBASE, and the Cochrane Library with restrictions to articles in English language databases were searched to retrieve available data. Results: There are limited data in literature regarding in vitro and in vivo studies that examined the ability of cancer cells to take up L-glucose. Research work so far has shown that that the binding of a fluorescent detector to L-glucose molecule produced a fluorescent probe that was specifically taken up by malignant cancer cells, thus providing a unique method for their detection. Conclusion: Given that L-glucose is taken up by cancer cells, L-glucose fluorescent probes can be a useful tool for visualization and characterization of cancer cells. More research on the potential biologic effects of L-glucose in cancer is necessary.

scholarly journals O-GlcNAcylation destabilizes the active tetrameric PKM2 to promote the Warburg effect

2017 ◽  
Vol 114 (52) ◽  
pp. 13732-13737 ◽  
Author(s):  
Yang Wang ◽  
Jia Liu ◽  
Xin Jin ◽  
Dapeng Zhang ◽  
Dongxue Li ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Nuclear Translocation ◽  
Lactate Production ◽  
Human Tumor ◽  
Glucose Consumption ◽  
Metabolic Reprogramming ◽  
Proliferating Cells ◽  
The Warburg Effect

The Warburg effect, characterized by increased glucose uptake and lactate production, is a well-known universal across cancer cells and other proliferating cells. PKM2, a splice isoform of the pyruvate kinase (PK) specifically expressed in these cells, serves as a major regulator of this metabolic reprogramming with an adjustable activity subjected to numerous allosteric effectors and posttranslational modifications. Here, we have identified a posttranslational modification on PKM2, O-GlcNAcylation, which specifically targets Thr405 and Ser406, residues of the region encoded by the alternatively spliced exon 10 in cancer cells. We show that PKM2 O-GlcNAcylation is up-regulated in various types of human tumor cells and patient tumor tissues. The modification destabilized the active tetrameric PKM2, reduced PK activity, and led to nuclear translocation of PKM2. We also observed that the modification was associated with an increased glucose consumption and lactate production and enhanced level of lipid and DNA synthesis, indicating that O-GlcNAcylation promotes the Warburg effect. In vivo experiments showed that blocking PKM2 O-GlcNAcylation attenuated tumor growth. Thus, we demonstrate that O-GlcNAcylation is a regulatory mechanism for PKM2 in cancer cells and serves as a bridge between PKM2 and metabolic reprogramming typical of the Warburg effect.

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