1. STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications
- Author
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David A. Frank and Isidora Tošić
- Subjects
Cancer Research ,p53, tumor protein 53 ,MEF2D, Myocyte Enhancer Factor 2D ,FASN, fatty acid synthase ,OXPHOS, oxidative phosphorylation ,ERH, enhancer of rudimentary homolog ,PDGF, platelet-derived growth factor ,PFK, phosphofructokinase ,CREB, cyclic AMP response element-binding protein ,HDL-C, high-density lipoprotein cholesterol ,chemistry.chemical_compound ,PC, phosphatidylcholine ,GRIM-19, gene associated with retinoid-IFN-induced mortality ,Neoplasms ,Transcriptional regulation ,TGFβ, transforming growth factor beta ,AML, acute myeloid leukemia ,RC254-282 ,CDK, cyclin-dependent kinase ,FABP6, fatty acid binding protein 6 ,BCL, B-cell lymphoma ,CLL, chronic lymphocytic leukemia ,Chemistry ,LIF, leukemia inhibitory factor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,VEGF, vascular endothelial growth factor ,FBP1, fructose-bisphosphatase 1 ,GPI, glucose-6-phosphate isomerase ,Cell biology ,MMP, matrix metalloproteinase ,STAT, signal transducer and activator of transcription ,GAPDH, glyceraldehyde-3-phosphate dehydrogenase ,GP130, glycoprotein 130 ,Phosphorylation ,NHL, non-Hodgkin's lymphoma ,JAK, Janus kinase ,Adenosine triphosphate ,CNTF, ciliary neurotrophic factor ,STAT3 Transcription Factor ,ATP, adenosine triphosphate ,TAG, triacylglycerol ,Protein processing, Post-translational ,PPARγ, peroxisome proliferator-activated receptor gamma ,ETC, electron transport chain ,TNFα, tumor necrosis factor alpha ,RIME, rapid immunoprecipitation mass spectrometry of endogenous proteins ,GLUT1, glucose transporter 1 ,PGK1, phosphoglycerate kinase ,MPTP, mitochondrial permeability transition pore ,Mediator ,Review article ,CML, chronic myeloid leukemia ,HIF1α, hypoxia inducible factor 1α ,PIAS, protein inhibitors of activated STATs ,SOCS, suppressors of cytokine signaling ,Animals ,Humans ,IFN, interferon ,LDHA, lactate dehydrogenase A ,Transcription factor ,PKCδ, protein kinase C δ ,TF, transcription factors ,EGF, epidermal growth factor ,SM, sphingomyelin ,SREBP1, sterol regulatory element-binding protein 1 ,IAP, inhibitor of apoptosis ,PTP, protein tyrosine phosphatases ,Tyrosine phosphorylation ,Lipid metabolism ,BCSC, breast cancer stem cells ,IL, interleukin ,Metabolism ,OSM, oncostatin M ,Anaerobic glycolysis ,NFκB, nuclear factor kappa B ,TBK1, TANK-binding kinase 1 ,MCL, myeloid cell leukemia ,LDL-C, low-density lipoprotein cholesterol ,PBP, PPARγ binding protein ,CPT1B, carnitine palmitoyltransferase 1B ,FAO, fatty acid oxidation - Abstract
The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is activated constitutively in a wide array of human cancers. It is an appealing molecular target for novel therapy as it directly regulates expression of genes involved in cell proliferation, survival, angiogenesis, chemoresistance and immune responsiveness. In addition to these well-established oncogenic roles, STAT3 has also been found to mediate a wide array of functions in modulating cellular behavior. The transcriptional function of STAT3 is canonically regulated through tyrosine phosphorylation. However, STAT3 phosphorylated at a single serine residue can allow incorporation of this protein into the inner mitochondrial membrane to support oxidative phosphorylation (OXPHOS) and maximize the utility of glucose sources. Conflictingly, its canonical transcriptional activity suppresses OXPHOS and favors aerobic glycolysis to promote oncogenic behavior. Apart from mediating the energy metabolism and controversial effects on ATP production, STAT3 signaling modulates lipid metabolism of cancer cells. By mediating fatty acid synthesis and beta oxidation, STAT3 promotes employment of available resources and supports survival in the conditions of metabolic stress. Thus, the functions of STAT3 extend beyond regulation of oncogenic genes expression to pleiotropic effects on a spectrum of essential cellular processes. In this review, we dissect the current knowledge on activity and mechanisms of STAT3 involvement in transcriptional regulation, mitochondrial function, energy production and lipid metabolism of malignant cells, and its implications to cancer pathogenesis and therapy.
- Published
- 2021