The Warburg effect: Insights from the past decade

Upadhyay, Mohita; Samal, Jasmine; Kandpal, Manish; Singh, Om V.; Vivekanandan, Perumal

doi:10.1016/j.pharmthera.2012.11.003

Cited by 198 publications

(146 citation statements)

References 193 publications

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“…60 The pentose phosphate pathway and glucose-6-phosphate both contribute to the Warburg effect in cancer cell metabolism. 61 However, whether the Warburg effect plays an etiological role in cancer remains unclear. 61,62 Therefore, we cannot conclude whether the genes involved in metabolism that were upregulated in survivin-positive activated B cell-like diffuse large B-cell lymphoma patients should be considered to be a result or the cause of survivin overexpression.…”

Section: Discussionmentioning

confidence: 99%

“…61 However, whether the Warburg effect plays an etiological role in cancer remains unclear. 61,62 Therefore, we cannot conclude whether the genes involved in metabolism that were upregulated in survivin-positive activated B cell-like diffuse large B-cell lymphoma patients should be considered to be a result or the cause of survivin overexpression. Additional studies are needed to clarify the mechanisms underlying the difference in survival between survivin-positive and survivinnegative activated B cell-like diffuse large B-cell lymphoma patients.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

et al. 2015

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Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of 425%, associated with an International Prognostic Index score of 42 (P = 0.015), disease in ≥ 2 extranodal sites (P = 0.011), and a high Ki-67 index (Po 0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivinnegative patients (P = 0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P = 0.035 and P = 0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

et al. 2015

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“…In rapidly proliferating cells such as cancer cells, a metabolic switch called the Warburg effect is occurring. Under these conditions, glycolysis is uncoupled from the TCA cycle but coupled with lactate fermentation, and glycolytic rates increase to produce high levels of ATP in the cytosol (Upadhyay et al, 2013;Maldonado and Lemasters, 2014). Similarly, when T-cells are proliferating, lower rates of respiration and higher rates of glycolysis are observed (Kami nski et al, 2012).…”

Section: Regulation Of Respiratory Pathwaysmentioning

confidence: 99%

Complete Mitochondrial Complex I Deficiency Induces an Up-Regulation of Respiratory Fluxes That Is Abolished by Traces of Functional Complex I

Kühn

Obata²,

Feher³

et al. 2015

Plant Physiol.

104

116

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Complex I (NADH:ubiquinone oxidoreductase) is central to cellular NAD + recycling and accounts for approximately 40% of mitochondrial ATP production. To understand how complex I function impacts respiration and plant development, we isolated Arabidopsis (Arabidopsis thaliana) lines that lack complex I activity due to the absence of the catalytic subunit NDUFV1 (for NADH:ubiquinone oxidoreductase flavoprotein1) and compared these plants with ndufs4 (for NADH:ubiquinone oxidoreductase Fe-S protein4) mutants possessing trace amounts of complex I. Unlike ndufs4 plants, ndufv1 lines were largely unable to establish seedlings in the absence of externally supplied sucrose. Measurements of mitochondrial respiration and ATP synthesis revealed that compared with ndufv1, the complex I amounts retained by ndufs4 did not increase mitochondrial respiration and oxidative phosphorylation capacities. No major differences were seen in the mitochondrial proteomes, cellular metabolomes, or transcriptomes between ndufv1 and ndufs4. The analysis of fluxes through the respiratory pathway revealed that in ndufv1, fluxes through glycolysis and the tricarboxylic acid cycle were dramatically increased compared with ndufs4, which showed near wild-type-like fluxes. This indicates that the strong growth defects seen for plants lacking complex I originate from a switch in the metabolic mode of mitochondria and an up-regulation of respiratory fluxes. Partial reversion of these phenotypes when traces of active complex I are present suggests that complex I is essential for plant development and likely acts as a negative regulator of respiratory fluxes.In most eukaryotic organisms, energy is mainly provided by cellular respiration, which is composed of three main pathways. Glycolysis in the cytosol, and additionally in the plastids of plants, degrades sugars into pyruvate. The tricarboxylic acid (TCA) cycle, which largely resides in the mitochondrial matrix, further dissimilates pyruvate into CO 2 . These two pathways generate reduced cofactors, mostly NADH. The oxidative phosphorylation (OXPHOS) system couples cofactor recycling with ATP production. The electron transfer chain (ETC) located in the mitochondrial inner membrane (IM) uses the redox energy of the reduced cofactors to create an electrochemical gradient across the IM. This gradient is then used by the ATP synthase to convert ADP to ATP, which is subsequently exported from the mitochondria to fuel cellular metabolism and sustain housekeeping functions and growth.The ETC is composed of four large multiprotein complexes. The first of these complexes is the NADHubiquinone oxidoreductase, also called complex I. It plays a crucial role in recycling NAD + for the TCA cycle, and its activity is responsible for about 40% of the total proton pumping across the IM (Wikström, 1984;Galkin et al., 2006). In plants, additional NADH dehydrogenases located on both sides of the IM are present (for review, see Rasmusson et al., 2008). These enzymes can recycle NAD + for use in glycolysis and the TCA cyc...

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“…The Warburg effect, also known as aerobic glycolysis, is an emerging hallmark of tumor cell metabolism (4)(5)(6). Lactate dehydrogenase A (LDHA) is a key enzyme in aerobic glycolysis that increases glucose uptake and lactate production in tumor cells; LDHA has attracted increasing attention in recent years due to its critical role in tumor progression (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Silencing LDHA inhibits proliferation, induces apoptosis and increases chemosensitivity to temozolomide in glioma cells

Zhang

Guo

et al. 2018

Oncol Lett

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Abstract. Glioblastoma multiforme (GBM) is a prevalent and aggressive disease, and the development of a novel therapy to better treat advanced GBM is urgently required. Lactate dehydrogenase A (LDHA), which functions as a key enzyme in transforming pyruvate into lactate, has attracted more attention in recent years due to its critical role in various types of advanced cancer. Previous data derived from the Oncomine database have shown that the expression of LDHA is higher in GBM tissues than that in corresponding normal control tissues. However, the association of LDHA levels with glioma clinical grades and the possible mechanisms of LDHA in GBM progression have not been investigated. The present study showed that there is a significant positive correlation between LDHA expression levels and tumor clinical stages. The knockdown of LDHA inhibited cell growth by inhibiting cell cycle progression and inducing apoptosis in glioma cell lines. Upon investigating the molecular mechanism, LDHA knockdown via siRNA treatment was associated with decreased cyclin D1 expression, increased cleavage of PARP, and altered B-cell lymphoma 2 and B-cell lymphoma 2-associated protein X expression. In addition, LDHA knockdown led to the marked downregulation of matrix metalloproteinase (MMP)-2, MMP-9, VE-Cadherin and vascular endothelial growth factor expression levels. Furthermore, knock down of LDHA enhanced the chemosensitivity of glioma cells to temozolomide (TMZ), a second-generation alkylating agent with activity against recurrent high-grade glioma. These findings support LDHA as a novel target for developing effective therapeutic strategies to treat GBM.

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The Warburg effect: Insights from the past decade

Cited by 198 publications

References 193 publications

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

Complete Mitochondrial Complex I Deficiency Induces an Up-Regulation of Respiratory Fluxes That Is Abolished by Traces of Functional Complex I

Silencing LDHA inhibits proliferation, induces apoptosis and increases chemosensitivity to temozolomide in glioma cells

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