Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance

Burns, Jorge S.; Manda, Gina

doi:10.3390/ijms18122755

Cited by 129 publications

(110 citation statements)

References 166 publications

(166 reference statements)

Supporting

Mentioning

101

Contrasting

Unclassified

Order By: Relevance

“…Several c-Myc targets modulated by PEP/Ca 2+ (i.e., Glut1, LDH-A) are associated with clinical colorectal cancer progression [35] and are also induced by K-Ras, commonly mutated in these cancers. Regulation of other targets such as glutaminase (GLS1) and the cytosolic isoform of serine hydroxymethyltransferase (cSHMT) suggest changes in the metabolic layout in agreement with the Warburg effect phenotype [23,36]. This is consistent with the need for double inhibition of c-Myc and PI3K signaling pathways to reduce glucose uptake and glycolytic flux in lymphoma cell lines [37].…”

Section: Discussionsupporting

confidence: 58%

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Moreno-Felici

Hyroššová

Aragó

et al. 2019

Cells

View full text Add to dashboard Cite

Changes in phosphoenolpyruvate (PEP) concentrations secondary to variations in glucose availability can regulate calcium signaling in T cells as this metabolite potently inhibits the sarcoplasmic reticulum Ca 2+ /ATPase pump (SERCA). This regulation is critical to assert immune activation in the tumor as T cells and cancer cells compete for available nutrients. We examined here whether cytosolic calcium and the activation of downstream effector pathways important for tumor biology are influenced by the presence of glucose and/or cataplerosis through the phosphoenolpyruvate carboxykinase (PEPCK) pathway, as both are hypothesized to feed the PEP pool. Our data demonstrate that cellular PEP parallels extracellular glucose in two human colon carcinoma cell lines, HCT-116 and SW480. PEP correlated with cytosolic calcium and NFAT activity, together with transcriptional up-regulation of canonical targets PTGS2 and IL6 that was fully prevented by CsA pre-treatment. Similarly, loading the metabolite directly into the cell increased cytosolic calcium and NFAT activity. PEP-stirred cytosolic calcium was also responsible for the calmodulin (CaM) dependent phosphorylation of c-Myc at Ser62, resulting in increased activity, probably through enhanced stabilization of the protein. Protein expression of several c-Myc targets also correlated with PEP levels. Finally, the participation of PEPCK in this axis was interrogated as it should directly contribute to PEP through cataplerosis from TCA cycle intermediates, especially in glucose starvation conditions. Inhibition of PEPCK activity showed the expected regulation of PEP and calcium levels and consequential downstream modulation of NFAT and c-Myc activities. Collectively, these results suggest that glucose and PEPCK can regulate NFAT and c-Myc activities through their influence on the PEP/Ca 2+ axis, advancing a role for PEP as a second messenger communicating metabolism, calcium cell signaling, and tumor biology.

show abstract

Section: Discussionsupporting

confidence: 58%

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Moreno-Felici

Hyroššová

Aragó

et al. 2019

Cells

View full text Add to dashboard Cite

show abstract

“…The major oncogene Ras, when mutated, can also induce glycolysis through the activation of the mammalian target of rapamycin complex I (mTORC1). Akt kinase activation by PI3K results in increased glucose uptake, HK2 targeting to the mitochondria, and increase in glycolytic flux (34), while the transcription factor MYC increases glutaminolysis and upregulates MCT1 expression (35). Cancer cell metabolism is also influenced by the activity of tumor suppressor genes.…”

Section: Oncogenic Triggers Of Glycolytic Metabolismmentioning

confidence: 99%

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

et al. 2020

View full text Add to dashboard Cite

To sustain their high proliferation rates, most cancer cells rely on glycolytic metabolism, with production of lactic acid. For many years, lactate was seen as a metabolic waste of glycolytic metabolism; however, recent evidence has revealed new roles of lactate in the tumor microenvironment, either as metabolic fuel or as a signaling molecule. Lactate plays a key role in the different models of metabolic crosstalk proposed in malignant tumors: among cancer cells displaying complementary metabolic phenotypes and between cancer cells and other tumor microenvironment associated cells, including endothelial cells, fibroblasts, and diverse immune cells. This cell metabolic symbiosis/slavery supports several cancer aggressiveness features, including increased angiogenesis, immunological escape, invasion, metastasis, and resistance to therapy. Lactate transport is mediated by the monocarboxylate transporter (MCT) family, while another large family of G protein-coupled receptors (GPCRs), not yet fully characterized in the cancer context, is involved in lactate/acidosis signaling. In this mini-review, we will focus on the role of lactate in the tumor microenvironment, from metabolic affairs to signaling, including the function of lactate in the cancer-cancer and cancer-stromal shuttles, as well as a signaling oncometabolite. We will also review the prognostic value of lactate metabolism and therapeutic approaches designed to target lactate production and transport.

show abstract

“…A metabolic shift towards aerobic glycolysis is a hallmark of cancer progression (Burns and Manda, 2017;Liberti and Locasale, 2016). Our data demonstrated that the loss of NCLX leads to reduced oxygen consumption, increased glycolysis, and increased transcription of major glycolytic enzymes (Figure 5J, 6B, C and 8).…”

Section: Discussionmentioning

confidence: 60%

Colorectal adenocarcinomas downregulate the mitochondrial Na⁺/Ca²⁺ exchanger NCLX to drive metastatic spread

Pathak

Guéguinou

Walter

et al. 2020

Preprint

View full text Add to dashboard Cite

Highlights• The expression of NCLX is decreased in colorectal tumors and is associated with advanced-stage disease in patients. • NCLX plays a dichotomous role in colorectal tumor growth and metastasis.• NCLX downregulation causes mitophagy and reduced colorectal cancer tumor growth.• NCLX downregulation induces stemness, chemoresistance and metastasis through mtCa 2+ /ROS/HIF1α signaling axis. Graphical Abstract SummaryDespite the established role of mitochondria in tumorigenesis, the molecular mechanisms by which mitochondrial Ca 2+ (mtCa 2+ ) signaling regulates tumor growth and metastasis remain unknown. The crucial role of mtCa 2+ in tumorigenesis is highlighted by the altered expression of proteins mediating mtCa 2+ uptake and extrusion in cancer cells. Here, we demonstrate that expression of the mitochondrial Na + /Ca 2+ exchanger NCLX (SLC8B1) is decreased in colorectal tumors and is associated with advanced-stage disease in patients. We reveal that downregulation of NCLX leads to mtCa 2+ overload, mitochondrial depolarization, mitophagy, and reduced tumor size. Concomitantly, NCLX downregulation drives metastatic spread, chemoresistance, the expression of epithelial-to-mesenchymal transition (EMT), hypoxia, and stem cell pathways. Mechanistically, mtCa 2+ overload leads to an increase in mitochondrial reactive oxygen species (mtROS) which activates HIF1α signaling supporting the metastatic behavior of tumor cells lacking NCLX. Our results reveal that loss of NCLX expression is a novel driver of metastatic progression, indicating that control of mtCa 2+ levels is a novel therapeutic approach in metastatic colorectal cancer. SignificanceMitochondrial Ca 2+ (mtCa 2+ ) homeostasis is essential for cellular metabolism and growth and plays a critical role in cancer progression. mtCa 2+ uptake is mediated by an inner membrane protein complex containing the mitochondrial Ca 2+ uniporter (MCU). mtCa 2+ uptake by the MCU is followed by a ∼100-fold slower mtCa 2+ extrusion mediated by the inner mitochondrial membrane ion transporter, the mitochondrial Na + /Ca 2+ exchanger NCLX. Because NCLX is a slower transporter than the MCU, it is a crucial rate-limiting factor of mtCa 2+ homeostasis that cannot easily be compensated by another Ca 2+ transport mechanism. This represents the first study investigating the role of NCLX in tumorigenesis and metastasis. We demonstrate for the first time that colorectal cancers exhibit loss of NCLX expression and that this is associated with advancedstage disease. Intriguingly, decreased NCLX function has a dichotomous role in colorectal cancer. Thus, we reveal that NCLX loss leads to reduced primary tumor growth and overall tumor burden in vivo. Yet, the consequential increases in mtCa 2+ elicit pro-survival, hypoxic and gene transcription pathways that enhance metastatic progression. This dichotomy is a well-established feature of chemoresistant and recurrent tumor cells including cancer stem cells. Moreover, the downstream changes elicited by NCLX loss are reminiscent of mesenchym...

show abstract

Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance

Cited by 129 publications

References 166 publications

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

Colorectal adenocarcinomas downregulate the mitochondrial Na⁺/Ca²⁺ exchanger NCLX to drive metastatic spread

Contact Info

Product

Resources

About

Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance

Cited by 129 publications

References 166 publications

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

Colorectal adenocarcinomas downregulate the mitochondrial Na+/Ca2+ exchanger NCLX to drive metastatic spread

Contact Info

Product

Resources

About

Colorectal adenocarcinomas downregulate the mitochondrial Na⁺/Ca²⁺ exchanger NCLX to drive metastatic spread