Wnt/Snail Signaling Regulates Cytochrome<i>c</i>Oxidase and Glucose Metabolism

Lee, Su Yeon; Jeon, Hyun Min; Ju, Min Kyung; Kim, Cho Hee; Yoon, Gyesoon; Han, Song Iy; Park, Hye Gyeong; Kang, Ho Sung

doi:10.1158/0008-5472.can-12-0006

Cited by 176 publications

(172 citation statements)

References 50 publications

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“…Increasing the expression of COX-2 and its product PGE2 activates the b-catenin/TCF4 pathway and has been implicated in cancer tumorigenesis and EMT. 54,55 Our findings confirmed that the expression of PLC-g2 and TCF4 was increased after NPC cells were co-cultured with T-MDSCs but decreased in siCOX-2-treated cancer cells. Therefore, T-MDSCs induce EMT via the showing that tumoractivated MDSCs induce EMT via multiple pathways, including TGFb, HGH, and TGH, in melanoma.…”

Section: Discussionsupporting

confidence: 75%

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

OuYang

et al. 2015

OncoImmunology

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Keywords: COX-2, myeloid-derived suppressor cells, nasopharyngeal carcinomaAbbreviations: ARG-1, arginase 1; COX-2, cyclooxygenase-2; DFS, disease-free survival; EMT, epithelial-mesenchymal transition; GM-CSF, granulocyte-monocyte-colony stimulating factor; iNOS, inducible nitric oxide synthase; LNMMA, L-NG-monomethylarginine; MDSCs, myeloid-derived suppressor cells; NAC, N-acetylcysteine; NOHA, N-hydroxy-nor-L-arginine; NOX2, NADPH oxidase; NPC, nasopharyngeal carcinoma; ROS, reactive oxygen species; siRNA, small interfering RNA; TCF4, T-cell factor 4; TGF, transforming growth factor b; T-MDSCs, tumor-induced MDSCs; VEGF, vascular endothelial growth factorThe expansion of myeloid-derived suppressor cells (MDSCs) is a common feature of cancer, but its biological roles and molecular mechanism remain unclear. Here, we investigated a molecular link between MDSC expansion and tumor cell metastasis in nasopharyngeal carcinoma (NPC). We demonstrated that MDSCs expanded and were positively correlated with the elevated tumor COX-2 expression and serum IL-6 levels in NPC patients. Importantly, COX-2 and MDSCs were poor predictors of patient disease-free survival (DFS). Knocking down tumor COX-2 expression hampered functional TW03-mediated-MDSC cell (T-MDSC) induction with IL-6 blocking. We identified that T-MDSCs promoted NPC cell migration and invasion by triggering the epithelial-mesenchymal transition (EMT) on cell-to-cell contact, and TMDSCs enhanced tumor experimental lung metastasis in vivo. Interestingly, the contact between T-MDSCs and NPC cells enhanced tumor COX-2 expression, which subsequently activated the b-catenin/TCF4 pathway, resulting in EMT of the cancer cells. Blocking transforming growth factor b (TGFb) or inducible nitric oxide synthase (iNOS) significantly abolished the T-MDSC-induced upregulation of COX-2 and EMT scores in NPC cells, whereas the administration of TGFb or L-arginine supplements upregulated COX-2 expression and EMT scores in NPC cells. These findings reveal that COX-2 is a key factor mediating the interaction between MDSCs and tumor cells, suggesting that the inhibition of COX-2 or MDSCs has the potential to suppress NPC metastasis.

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Section: Discussionsupporting

confidence: 75%

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

OuYang

et al. 2015

OncoImmunology

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“…In this study it was reported that the activation of Wnt repressed mitochondrial cytochrome oxidase (COX) expression con-comitantly with the stimulation of lactate production. Surprisingly, PC expression was enhanced, suggesting a possible activation of the anaplerotic pathways [81]. These results seem contradictory as they imply the induction of the aerobic glycolysis, while anaplerosis is indicative of a high Krebs cycle activity.…”

Section: Pyruvate Carboxylasementioning

confidence: 88%

Anaplerosis in cancer: Another step beyond the warburg effect

Ochoa-Ruiz¹,

Díaz-Ruiz²

2012

AJMB

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Biosynthesis is up-regulated in tumors and thus the demand for anabolic intermediates is increased. The metabolic routes providing the building blocks for macromolecules are thus a very attractive target as they are not normally up-regulated in a normal quiescent cell. Some routes for glycolysis-derived intermediates production have been identified, but these do not constitute the whole pool of biosynthetic molecules in the cell, as many of these derive from mitochondria in the Krebs cycle. Indeed, this metabolic pathway is considered a "biosynthetic hub" from which anabolism is fed. If a metabolite efflux is indeed occurring, anaplerotic reactions must keep a steady supply of substrates. In spite of this obvious relevance of anaplerosis, it has been poorly characterized in the malignant cell context. Glutaminolysis and and pyruvate carboxylation are two pathways that function in an anaplerotic fashion. In spite of the increasing evidence implicating these two processes in cancer metabolism their role as intermediate providers is overlooked. In this review we analyze the implications of an active anaplerosis in cancer and we discuss experimental evidence showing the relevance of these metabolic routes in tumor physiology.

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“…However, more recently, direct associations have been demonstrated for control of cancer cell metabolism by the canonical WNT pathway. In breast cancer, for example, WNT/␤-catenin signaling increases aerobic glycolysis through suppression of mitochondrial respiration by reducing the transcription of the gene for cytochrome c oxidase, which is an integral enzyme of the ETC and thus essential for OXPHOS (12). Furthermore, in triple-negative breast cancer cells, WNT5B was recently shown to be able to control the expression of the OX-PHOS-related genes for cytochrome c 1 and the ATP synthase ␥ subunit through the canonical WNT pathway (15).…”

Section: Canonical Wnt Signaling and Cancer Cell Metabolismmentioning

confidence: 99%

“…Recently, evidence has emerged that highlights a role for WNT-mediated regulation of cellular metabolism as well, including the reprogramming of tumor cell bioenergetics (12)(13)(14)(15). This review explores the evidence that components of the WNT signaling pathways regulate cellular metabolism with a specific focus on cancer cells.…”

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confidence: 99%

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

Sherwood

2015

Molecular and Cellular Biology

129

105

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WNT signaling was discovered in tumor models and has been recognized as a regulator of cancer development and progression for over 3 decades. Recent work has highlighted a critical role for WNT signaling in the metabolic homeostasis of mammals, where its misregulation has been heavily implicated in diabetes. While the majority of WNT metabolism research has focused on nontransformed tissues, the role of WNT in cancer metabolism remains underinvestigated. Cancer is also a metabolic disease where oncogenic signaling pathways regulate energy production and macromolecular synthesis to fuel rapidly proliferating tumors. This review highlights the emerging evidence for WNT signaling in the reprogramming of cancer cell metabolism and examines the role of these signaling pathways as mediators of tumor bioenergetics.

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Wnt/Snail Signaling Regulates CytochromecOxidase and Glucose Metabolism

Cited by 176 publications

References 50 publications

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

Anaplerosis in cancer: Another step beyond the warburg effect

WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

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