Actuality of Warburg’s views in our understanding of renal cancer metabolism

More than 50 years ago, Warburg proposed that the shift in glucose metabolism from oxidative phosphorylation (OXPHOS) to glycolysis occurring in spite of an adequate oxygen supply was at the root of cancer. This hypothesis often disregarded over the following years has recently stirred up much interest due to progress made in cancer genetics and proteomics. Studies related to renal cancers have been particularly informative to understand how abnormal use of glucose and decrease in OXPHOS are linked to cell proliferation in tumors. Indeed, in aggressive tumors such as clear cell renal carcinoma, the von Hippel–Lindau factor invalidation stabilizes the hypoxia-inducible factor (HIF) in the presence of oxygen. HIF stimulating glycolytic gene expression increases the glycolytic flux. Deficiencies in genes involved in oxidative phosphorylation that can explain the down-regulation of OXPHOS components also begin to be identified. These findings are important in the search for novel therapeutic approaches to cancer treatment.     

Positive feedback in Cav‐1‐ROS signalling in PSCs mediates metabolic coupling between PSCs and tumour cells

Caveolin‐1 (Cav‐1) is the principal structural component of caveolae, and its dysregulation occurs in cancer. However, the role of Cav‐1 in pancreatic cancer (PDAC) tumorigenesis and metabolism is largely unknown. In this study, we aimed to investigate the effect of pancreatic stellate cell (PSC) Cav‐1 on PDAC metabolism and aggression. We found that Cav‐1 is expressed at low levels in PDAC stroma and that the loss of stromal Cav‐1 is associated with poor survival. In PSCs, knockdown of Cav‐1 promoted the production of reactive oxygen species (ROS), while ROS production further reduced the expression of Cav‐1. Positive feedback occurs in Cav‐1‐ROS signalling in PSCs, which promotes PDAC growth and induces stroma‐tumour metabolic coupling in PDAC. In PSCs, positive feedback in Cav‐1‐ROS signalling induced a shift in energy metabolism to glycolysis, with up‐regulated expression of glycolytic enzymes (hexokinase 2 (HK‐2), 6‐phosphofructokinase (PFKP) and pyruvate kinase isozyme type M2 (PKM2)) and transporter (Glut1) expression and down‐regulated expression of oxidative phosphorylation (OXPHOS) enzymes (translocase of outer mitochondrial membrane 20 (TOMM20) and NAD(P)H dehydrogenase [quinone] 1 (NQO1)). These events resulted in high levels of glycolysis products such as lactate, which was secreted by up‐regulated monocarboxylate transporter 4 (MCT4) in PSCs. Simultaneously, PDAC cells took up these glycolysis products (lactate) through up‐regulated MCT1 to undergo OXPHOS, with down‐regulated expression of glycolytic enzymes (HK‐2, PFKP and PKM2) and up‐regulated expression of OXPHOS enzymes (TOMM20 and NQO1). Interrupting the metabolic coupling between the stroma and tumour cells may be an effective method for tumour therapy.     

Immune effects of glycolysis or oxidative phosphorylation metabolic pathway in protecting against bacterial infection

The metabolism of immune cells reprograms inflammatory responses to protect against infection by pathogenic microorganisms, but the immune effects of glycolysis and the oxidative phosphorylation (OXPHOS) metabolic pathway remain unclear. Herein, the effects of glycolysis or OXPHOS on the neutrophils and T cells were investigated using a pharmacological approach in mice. 2-Deoxy-d -glucose (2-DG), which blocks the key enzyme hexokinase of glycolysis, and dimethyl malonate (DMM), which blocks the key element succinate of OXPHOS, both efficiently expanded the population of neutrophils, but significantly inhibited tumor necrosis factor a secretion and reactive oxygen species (ROS) production. These compounds also effectively inhibited the differentiation of type 1 T helper cells (Th1) but had no effects on the differentiation of type 2 T helper cells (Th2) and regulatory T cells. A study of the underlying mechanism showed that hypoxia-inducible factor 1-alpha (HIF1α) was an upstream signal in the regulation of glycolysis, but not OXPHOS. In thioglycolate broth-induced neutrophil peritonitis, blockade of glycolysis or OXPHOS efficiently expanded the population of neutrophils, but diminished their abilities to secrete proinflammatory factors, produce ROS, and phagocytose bacteria. In Listeria monocytogenes bacteria-infected mice, 2-DG or DMM treatment consistently inhibited antibacterial activity and Th1 function. Thus, our results provide a basis for comprehensively understanding the role of glycolysis and OXPHOS in anti-infectious immunity.     

激活Toll样受体2可以促进胃癌细胞中的OXPHOS和糖酵解

目的:调查TLR家族中哪种TLR受体的配体依赖性激活可引起胃癌细胞的代谢重编程。方法:通过实时荧光定量PCR(RT-qPCR)和蛋白质印迹(WB)在一组人GC细胞中测量TLR家族成员的表达。通过进行Seahorse生物能测定以及测量L-乳酸和活性氧(ROS)的产生,确定激动剂对不同TLR(TLR2、4、9)诱导的人GC细胞的代谢变化;通过RT-qPCR在被刺激的GC细胞中分析了涉及氧化磷酸化和糖酵解的基因的表达;通过Western印迹表征SOD2的表达。结果:由合成分子或全病原体抗原激活的TLR2信号传导增强了胃癌细胞中高表达TLR2的细胞株的糖酵解活性和线粒体呼吸,而配体诱导的TLR4和TLR9活化抑制了线粒体呼吸或细胞外酸化率。同时,涉及葡萄糖代谢和氧化还原系统调节的基因,例如HIF1A,PFKFB3和SOD2,在TLRs下游被上调。结论:由配体诱导的特定TLRs的激活介导了人类GC细胞中不同的代谢表型。TLR2是唯一同时促进OXPHOS和糖酵解的家族成员,这可能导致肿瘤进展。     

The Warburg effect: Evolving interpretations of an established concept

Metabolic reprogramming and altered bioenergetics have emerged as hallmarks of cancer and an area of active basic and translational cancer research. Drastically upregulated glucose transport and metabolism in most cancers regardless of the oxygen supply, a phenomenon called the Warburg effect, is a major focuses of the research. Warburg speculated that cancer cells, due to defective mitochondrial oxidative phosphorylation (OXPHOS), switch to glycolysis for ATP synthesis, even in the presence of oxygen. Studies in the recent decade indicated that while glycolysis is indeed drastically upregulated in almost all cancer cells, mitochondrial respiration continues to operate normally at rates proportional to oxygen supply. There is no OXPHOS-to-glycolysis switch but rather upregulation of glycolysis. Furthermore, upregulated glycolysis appears to be for synthesis of biomass and reducing equivalents in addition to ATP production. The new finding that a significant amount of glycolytic intermediates is diverted to the pentose phosphate pathway (PPP) for production of NADPH has profound implications in how cancer cells use the Warburg effect to cope with reactive oxygen species (ROS) generation and oxidative stress, opening the door for anticancer interventions taking advantage of this. Recent findings in the Warburg effect and its relationship with ROS and oxidative stress controls will be reviewed. Cancer treatment strategies based on these new findings will be presented and discussed.     

An Overview: The Diversified Role of Mitochondria in Cancer Metabolism

Mitochondria are intracellular organelles involved in energy production, cell metabolism and cell signaling. They are essential not only in the process of ATP synthesis, lipid metabolism and nucleic acid metabolism, but also in tumor development and metastasis. Mutations in mtDNA are commonly found in cancer cells to promote the rewiring of bioenergetics and biosynthesis, various metabolites especially oncometabolites in mitochondria regulate tumor metabolism and progression. And mutation of enzymes in the TCA cycle leads to the unusual accumulation of certain metabolites and oncometabolites. Mitochondria have been demonstrated as the target for cancer treatment. Cancer cells rely on two main energy resources: oxidative phosphorylation (OXPHOS) and glycolysis. By manipulating OXPHOS genes or adjusting the metabolites production in mitochondria, tumor growth can be restrained. For example, enhanced complex I activity increases NAD⁺/NADH to prevent metastasis and progression of cancers. In this review, we discussed mitochondrial function in cancer cell metabolism and specially explored the unique role of mitochondria in cancer stem cells and the tumor microenvironment. Targeting the OXPHOS pathway and mitochondria-related metabolism emerging as a potential therapeutic strategy for various cancers.     

Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis

Cancer cells display high rates of aerobic glycolysis, a phenomenon known historically as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are highly produced by cancer cells even in the presence of oxygen. Hypoxia-induced gene expression in cancer cells has been linked to malignant transformation. Here we provide evidence that lactate and pyruvate regulate hypoxia-inducible gene expression independently of hypoxia by stimulating the accumulation of hypoxia-inducible Factor 1alpha (HIF-1alpha). In human gliomas and other cancer cell lines, the accumulation of HIF-1alpha protein under aerobic conditions requires the metabolism of glucose to pyruvate that prevents the aerobic degradation of HIF-1alpha protein, activates HIF-1 DNA binding activity, and enhances the expression of several HIF-1-activated genes including erythropoietin, vascular endothelial growth factor, glucose transporter 3, and aldolase A. Our findings support a novel role for pyruvate in metabolic signaling and suggest a mechanism by which high rates of aerobic glycolysis can promote the malignant transformation and survival of cancer cells.     

Artematrolide A inhibited cervical cancer cell proliferation via ROS/ERK/mTOR pathway and metabolic shift

BackgroundArtematrolide A (AR-A), a guaianolide dimer isolated from Artemisia atrovirens, demonstrated significant inhibitory effect on three human hepatoma cell lines (HepG2, Huh7 and SMMC7721). The anti-cervical cancer effect and mechanism of this compound have yet to be explored. This study is to reveal the role and mechanisms of artematrolide A on cervical cancer cells, and provide the pharmacological understanding of artematrolide A.PurposeTo investigate the function and possible mechanism of artematrolide A on cervical cancer cells in vitro.MethodsHeLa S3 and SiHa cells were treated with artematrolide A at various concentrations. In this study, MTT, colony formation, cell migration and invasion, cell cycle analysis, cell apoptosis, reactive oxygen species (ROS) detection, western blotting, enzyme activity, and lactate production of artematrolide A were evaluated.ResultsArtematrolide A inhibited cell viability, proliferation, migration and invasion in a dose-dependent manner, caused cell cycle arrest in G2/M phase, and induced cell apoptosis via Bcl-2/PARP-1. The mechanism of action of artematrolide A included two aspects: artematrolide A suppressed cell proliferation by activating ROS/ERK/mTOR signaling pathway and promoted glucose metabolism from aerobic glycolysis to mitochondrial respiration by activating pyruvate dehydrogenase complex (PDC) and oxoglutarate dehydrogenase complex (OGDC) via inhibiting the activity of alkaline phosphatases (ALP).ConclusionArtematrolide A exhibited a significant cytotoxic activity on cervical cancer cells, induced G2/M cell cycle arrest and apoptosis by activating ROS/ERK/mTOR signaling pathway and promoting metabolic shift from aerobic glycolysis to mitochondrial respiration, which suggested artematrolide A might be a potential agent for the treatment of cervical cancer.