Beyond Warburg effect – dual metabolic nature of cancer cells

Xie, Jiaxin; Wu, Hao; Dai, Chen; Pan, Qiangrong; Ding, Zonghui; Hu, Danqing; Ji, Bingyan; Luo, Yan; Hu, Xun

doi:10.1038/srep04927

Cited by 174 publications

(181 citation statements)

References 52 publications

Supporting

Mentioning

168

Contrasting

Order By: Relevance

“…Lactate is a critical substrate for supplying energy in cancer (via the Warburg effect), and is believed to help determine low pH during carcinogenesis (21). Furthermore, the activation of aerobic glycolysis can trigger lactate production, and as a byproduct, it can also supply nicotinamide adenine dinucleotide (NAD) + as a co-substrate for glycolysis which induce rapid cancer cell growth (22).…”

Section: U87mg Cells Favor Aerobic Glycolysis At the Transcriptional mentioning

confidence: 99%

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

Kim

Han

Jang

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

Abstract. Among the primary brain tumors, glioblastoma multiforme (GBM) has a radical proliferation ability that complicates the therapeutic modulation of cancer progression. The majority of GBM patients have a low survival rate (<1 year) due to radical tumor growth and late cancer diagnosis. Previous reports have shown that astrocytes have a specific metabolic organization that includes the production of lactate, the storage of glycogen, and use of lactate to support neurons which possess higher capacity of metabolism compared to neurons. We hypothesized that these characteristics of astrocytes could contribute to enhanced proliferation of GBM compared to neuroblastoma (NB). Here, we show that U87MG cells (a model of GBM) proliferate more rapidly than SH-SY5Y cells (a model of NB). A higher extracellular acidification rate and maximal mitochondrial oxygen consumption rate were observed in U87MG cells compared to SH-SY5Y cells. The expression levels of lactate dehydrogenase (LDH)-A and LDH-B were higher in U87MG cells and primary cultured astrocytes than in SH-SY5Y cells and neurons. Furthermore, the mRNA levels of succinate dehydrogenase and peroxisome proliferator-activated receptor-γ were high in U87MG cells, suggesting that these cells have high capacity for mitochondrial metabolism and uptake of fatty acids related to synthesis of the cell membrane, respectively. Taken together, we demonstrate that GBM cells are characterized by activation of the LDH-expression-related glycolytic pathway and mitochondrial metabolic capacity, suggesting two innate properties of astrocytes that could provide a driving force for the growth ability of GBM. Based on these findings, we propose that therapeutic approaches aimed at treating GBM could target LDH for modulating the metabolic properties of GBM cells.

show abstract

Section: U87mg Cells Favor Aerobic Glycolysis At the Transcriptional mentioning

confidence: 99%

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

Kim

Han

Jang

et al. 2015

International Journal of Oncology

View full text Add to dashboard Cite

show abstract

“…The fluxes were reflected by the amount of generated lactate. The amounts of generated lactate were determined by HPLC as described by us previously (25). For PKM2, assay, the condition was the same as above except that ADP concentration in the in vitro glycolytic system was 50 M.…”

Section: Metabolic Flux Control Assaymentioning

confidence: 99%

“…The action was terminated by adding 600 l 1 M HClO 4 , then neutralized with 100 l 3 M K 2 CO 3 , After keeping on ice for about 30 min and centrifugation, the supernatant obtained was analyzed for the lactate generated. When PKM2 was assayed, the reaction mixture was the same as above, except ADP was 50 M. The amounts of generated lactate were determined by HPLC as described by us previously (25).…”

Section: In Vitro Glycolytic Systemmentioning

confidence: 99%

Evidence That Does Not Support Pyruvate Kinase M2 (PKM2)-catalyzed Reaction as a Rate-limiting Step in Cancer Cell Glycolysis

Xie

Dai²,

Hu³

2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

It has been recognized that the rate-limiting function of pyruvate kinase M2 (PKM2) in glycolysis plays an important role in distributing glycolytic intermediates for anabolic and catabolic purposes in cancer cells. However, after analysis of the catalytic capacity of PKM2 relative to other glycolytic enzymes, the regulation range of PKM2 activity, metabolic flux control, and thermodynamics, we suggest that the PKM2-catalyzed reaction is not a rate-limiting step in cancer cell glycolysis. Hexokinase and phosphofructokinase 1 (PFK1), the first and third enzyme along the pathway, are rate-limiting enzymes that limit the overall glycolytic rate, whereas PKM2 and lactate dehydrogenase, the last two enzymes in the pathway, are for the fast removal of upstream intermediates to prevent the obstruction of the pathway. The argument is in accordance with the catalytic capacity of glycolytic enzymes, regulation range of enzyme activities, metabolic flux control, and thermodynamics.During tumorigenesis, pyruvate kinase (PK) isotype in cells switches from pyruvate kinase M1 (PKM1) or pyruvate kinase L (PKL) to PKM2 (1, 2), suggesting that PKM2 plays a part in tumor initiation and development. PK catalyzes the last step of glycolysis and is commonly regarded as a rate-limiting enzyme. In cancer cells, PKM2 is considered as a rate-limiting enzyme, because its enzyme activity is sensitive to allosteric regulation (3, 4) and it catalyzes a thermodynamically favorable reaction. It is proposed that when it is allosterically inhibited, its catalytic rate is lower than the upstream glycolytic rate; hence, phosphoenolpyruvate (PEP) 4 and upstream glycolytic intermediate may accumulate and flow to anabolic pathways; when it is allosterically activated, its activity is higher than the upstream glycolytic rate, and the upstream glycolytic intermediate would flow to pyruvate, which is then converted to lactate or enters mitochondria for complete oxidation. There are several lines of evidence that support this hypothesis (1, 4 -11).However, the evidence to support PKM2 as a rate-limiting enzyme is not sufficient. If PKM2 is a rate-limiting enzyme, the following lines of evidence are required: (a) PKM2 catalyzes an irreversible reaction; (b) its enzyme activity relative to other glycolytic enzymes is low; (c) its activity is sensitive to regulation; and (d) when its activity is allosterically activated, its catalytic rate should be higher than the upstream glycolytic rate and when its activity is allosterically inhibited, its catalytic rate should be lower than upstream glycolytic rate. So far, there is evidence of points a and c but no b and d.

show abstract

“…The metabolic shift to a higher rate of glycolysis can even be observed in patients with malignant tumors using positron emission tomography (PET) [5] . Beyond the current concept that the Warburg effect plays a central role in tumor metabolism, studies have shown that there may be dual metabolic (the Warburg effect and the nonglycolytic phenotype) natures in a given cell type, providing them with survival and growth advantages when adapting to a stressful microenvironment [6] . Cancer cells exhibit a glycolytic phenotype under regular conditions but can switch to a non-glycolytic phenotype under lactic acidosis.…”

Section: The Warburg Effect-a Hallmark Of Cancermentioning

confidence: 99%

“…In recent years, the concept of reversing the Warburg effect offers new perspectives to develop therapeutic strategies that focus on both of the targets, glycolysis and mitochondrial OXPHOS. Cancer cells can activate NFB and HIF-1α in adjacent stromal fibroblasts via oxidative stress promoted by ROS production, resulting in autophagy and mitophagy as well as glycolysis, which in turn can supply recycled nutrients to tumor cells for growth [6,55] . Therefore, it may be of significance to regulate glycolysis by targeting autophagy in the stroma.…”

Section: Anti-cancer Therapy Based On the Warburg Effectmentioning

confidence: 99%

Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

et al. 2016

View full text Add to dashboard Cite

Tumor cells rely mainly on glycolysis for energy production even in the presence of sufficient oxygen, a phenomenon termed the Warburg effect, which is the most outstanding characteristic of energy metabolism in cancer cells. This metabolic adaptation is believed to be critical for tumor cell growth and proliferation, and a number of onco-proteins and tumor suppressors, including the PI3K/Akt/mTOR signaling pathway, Myc, hypoxia-inducible factor and p53, are involved in the regulation of this metabolic adaptation. Moreover, glycolytic cancer cells are often invasive and impervious to therapeutic intervention. Thus, altered energy metabolism is now appreciated as a hallmark of cancer and a promising target for cancer treatment. A better understanding of the biology and the regulatory mechanisms of aerobic glycolysis has the potential to facilitate the development of glycolysis-based therapeutic interventions for cancer. In addition, glycolysis inhibition combined with DNA damaging drugs or chemotherapeutic agents may be effective anticancer strategies through weakening cell damage repair capacity and enhancing drug cytotoxicity.

show abstract

Beyond Warburg effect – dual metabolic nature of cancer cells

Cited by 174 publications

References 52 publications

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

Evidence That Does Not Support Pyruvate Kinase M2 (PKM2)-catalyzed Reaction as a Rate-limiting Step in Cancer Cell Glycolysis

Anticancer strategies based on the metabolic profile of tumor cells: therapeutic targeting of the Warburg effect

Contact Info

Product

Resources

About