The Warburg Effect, Lactate, and Nearly a Century of Trying to Cure Cancer

Spencer, Netanya Y.; Stanton, Robert C.

doi:10.1016/j.semnephrol.2019.04.007

Cited by 75 publications

(62 citation statements)

References 70 publications

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“…* p < 0.05 compared with vector-NC. Data are shown as mean ± standard deviation of three technical replicates metabolism, offering a favorable environment where cancer cells are attempting to grow, survive, proliferate, and maintain in a long term [29,30]. Consistently, our results showed that the anti-tumor effects of elevated PTEN expression were in parallel with inhibited Warburg effect as evidenced by decreased levels of glucose uptake and lactate.…”

Section: Discussionsupporting

confidence: 83%

Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma

et al. 2020

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Background: Metabolic reprogramming, in which energetic metabolism changes from oxidative phosphorylation to glycolysis, is well-accepted as a hallmark of cancers including hepatocellular carcinoma (HCC). A growing body of evidence suggests the involvement of oncogenes and tumor suppressor genes in the control of metabolic reprogramming. In this study, we attempt to investigate whether loss of PTEN, a recognized tumor suppressor, drives metabolic reprogramming of HCC. Methods: Cancerous liver tissues were surgically resected from 128 HCC patients, with 43 adjacent noncancerous liver tissues as control. Aerobic glycolysis (Warburg effect) was reflected by measurements of glucose uptake and lactate production, mitochondrial membrane potential collapse was observed by JC-1 staining, glycolytic rate and mitochondrial respiration were evaluated by determining glycolytic proton efflux rate (glycoPER) and oxygen consumption rate (OCR) in cultured human HHCC cells. Results: Reciprocal expression of PTEN and PI3K was determined in cancer liver tissues. Overexpression of PTEN suppressed the Warburg effect, as evidenced by reductions in glucose uptake and lactate production, maintenance of mitochondrial function, and transformation of energetic metabolism from glycolysis to oxidative phosphorylation in cultured PTEN-negative HHCC cells. Importantly, 740 Y-P, a PI3K agonist that leads to activation of the PI3K pathway, partially abrogated the function of PTEN and reprogramed glucose metabolism in cultured HHCC cells. Conclusions: The discovery that loss of PTEN allows the tumor metabolic program has been a major advance in understanding the carcinogenesis of HCC.

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Section: Discussionsupporting

confidence: 83%

Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma

et al. 2020

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“…37,38 Existing studies have proven that elevated GLUT1 expression is observed in most solid cancers. 4,[39][40][41][42] In our study, we further demonstrated the aberrant expression of GLUT1 in GC tissues, resulting GC progression. In Although our survival analysis confirmed that increased GLUT1 expression shortened the survival time of GC patients, which was in line with previous studies, 12 our subgroup analysis showed that the downtrend of survival probability of early GC patients without lymph node metastasis or TNM staging Ⅰ-Ⅱ was more apparent when Nomogram for the predication of survival probability of gastric cancer patients.…”

Section: Discussionsupporting

confidence: 67%

“…2,3 Cancer cells display enhanced glucose metabolism and prefer to generate ATP via glycolysis instead of oxidative phosphorylation even in the presence of oxygen. 4 The characteristic metabolic phenotype is known as aerobic glycolysis. 5 The glucose transporter (GLUT) family includes various homologous membrane proteins that transport glucose from the extracellular environment to the cytosol.…”

Section: Introductionmentioning

confidence: 99%

<p>Glucose Transporter-1 Cooperating with AKT Signaling Promote Gastric Cancer Progression</p>

Zhou¹,

Jiang²,

Jin³

et al. 2020

CMAR

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High expression of GLUT1 has been observed in numerous solid cancers, facilitating glucose consumption for supporting tumor cell survival. The altered metabolic activity is regulated by series of signaling pathways, including AKT signaling that acts as a key role in glucose metabolism and shows close correlation with the malignant transformation. In this study, we aimed to elucidate the effect of GLUT1 on gastric cancer (GC) and to explore the relation between GLUT1 and AKT signaling. Materials and Methods: GLUT1, p-AKT, and p-S6k1 expression were investigated by immunohistochemistry and semi-quantitative analysis in 57 paired-GC samples. The relationship of GLUT1 with clinical indexes in GC tissues was investigated. The effects of GLUT1 on the prognosis of GC patients and the underlying mechanism involved were studied by subgroup analysis. Results: In GC tissues, an obvious increase in GLUT1 expression was observed when compared with that of normal tissues (P<0.001). Advanced clinicopathological factors (tumor size P=0.019, invasion depth P=0.002, lymph node metastasis P<0.001, differentiation P=0.024, neural invasion P=0.003, and TNM staging P=0.001) correlated with high GLUT1 levels. GLUT1 was an independent risk factor resulting in poor prognosis (P=0.002, HR=5.132). GLUT1 increased the activation ratio of p-AKT (P<0.01) and p-S6K1 (P<0.001) in GC. The expression of p-S6K1 and GLUT1 was positively correlated. (P=0.001, R=0.173). The survival probability of GC patients with GLUT1(+)/p-S6K1(+) was worse when compared to that of GLUT1(+)/p-S6K1(-) or GLUT1 (-)/p-S6K1(+) (P<0.001). Conclusion: High expression of GLUT1 facilitated GC progression, leading to poor prognosis. Overexpression of GLUT1 activated AKT-S6K1 axis, resulting in adverse outcomes of GC. GLUT1 is novel indicator of GC prognosis and GLUT1 targeted metabolic treatment that has potential therapeutic value.

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“…The reprogramming of energy metabolism can serve as a hallmark in cancer physiology, making it possible for cancer cells to produce ATP whilst maintaining redox balance and macromolecular biosynthesis, processes that are necessary for cell proliferation, growth, migration, drug resistance and angiogenesis (20). It has been previously suggested that a large number of cancer types divert their energy metabolism towards the glycolytic pathway, resulting in the excessive production of lactate even under normoxic conditions, in a phenomenon known as the Warburg effect (21,22). Compared with non-malignant cells, cancer cells generally prefer incomplete and non-oxidative glucose metabolism (22).…”

Section: Identification Of a Prognosis-associated Signature Associatementioning

confidence: 99%

Identification of a prognosis‑associated signature associated with energy metabolism in triple‑negative breast cancer

et al. 2020

Oncol Rep

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At present, a large number of exciting results have been found regarding energy metabolism within the triple-negative breast cancer (TNBC) field. Apart from aerobic glycolysis, a number of other catabolic pathways have also been demonstrated to participate in energy generation. However, the prognostic value of energy metabolism for TNBC currently remains unclear. In the present study, the association between gene expression profiles of energy metabolism and outcomes in patients with TNBC was examined using datasets obtained from the Gene Expression Omnibus and The Cancer Genome Atlas. In total, four robust TNBC subtypes were identified on the basis of negative matrix factorization clustering and gene expression patterns, which exhibited distinct immunological, molecular and prognostic (disease-free survival) features. The differentially expressed genes were subsequently identified from the subgroup that demonstrated the poorest prognosis compared with the remaining 3 subgroups, where their biological functions were assessed further by means of gene ontology enrichment analysis. Any signatures found to be associated with energy metabolism were then established using the Cox proportional hazards model to assess patient prognosis. According to results of Kaplan-Meier analysis, the constructed signature consisting of eight genes that were associated with energy metabolism distinguished patient outcomes into low-and high-risk groups. In addition, this signature, which was found to be markedly associated with the clinical characteristics of the patients, served as an independent factor in predicting TNBC patient prognosis. According to gene set enrichment analysis, the gene sets related to the high-risk group participated in the MAPK signal transduction pathway, focal adhesion and extracellular matrix receptor interaction, whilst those related to the low-risk group were revealed to be mainly associated with mismatch repair and propanoate metabolism. Findings from the present study shed new light on the role of energy metabolism within TNBC, where the eight-gene signature associated with energy metabolism constructed can be utilized as a new prognostic marker for predicting survival in patients with TNBC.

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The Warburg Effect, Lactate, and Nearly a Century of Trying to Cure Cancer

Cited by 75 publications

References 70 publications

Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma

Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma

<p>Glucose Transporter-1 Cooperating with AKT Signaling Promote Gastric Cancer Progression</p>

Identification of a prognosis‑associated signature associated with energy metabolism in triple‑negative breast cancer

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