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Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment

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Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment Cancer Microenvironment (2019) 12:149–167 https://doi.org/10.1007/s12307-019-00226-0 REVIEW Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment Mohd Rihan1 & Lakshmi Vineela Nalla1 & Anil Dharavath1 & Amit Shard3 & Kiran Kalia2 & Amit Khairnar1 Received: 18 March 2019 /Accepted: 17 May 2019 /Published online: 10 June 2019 # Springer Nature B.V. 2019 Abstract Metabolic reprogramming is a newly emerged hallmark of cancer attaining a recent consideration as an essential factor for the progression and endurance of cancer cells. A prime event of this altered metabolism is increased glucose uptake and discharge of lactate into the cells surrounding constructing a favorable tumor niche. Several oncogenic factors help in promoting this consequence including, pyruvate kinase M2 (PKM2) a rate-limiting enzyme of glycolysis in tumor metabolism via exhibiting its low pyruvate kinase activity and nuclear moon-lightening functions to increase the synthesis of lactate and macromolecules for tumor proliferation. Not only its role in cancer cells but also its role in the tumor microenvironment cells has to be understood for developing the small molecules against it which is lacking with the literature till date. Therefore, in this present review, the role of PKM2 with respect to various tumor niche cells will be clarified. Further, it highlights the updated list of therapeutics targeting PKM2 pre-clinically and clinically with their added limitations. This upgraded understanding of PKM2 may provide a pace for the reader in developing chemotherapeutic strategies for better clinical survival with limited resistance. Keywords Metabolic reprogramming . PKM2 . Tumor microenvironment . Aerobic glycolysis . Tumor metabolism Abbreviations CD4 Cluster of differentiation 4 ANGPT2 Angiopoietin 2 COX-2 Cyclooxygenase-2 AKT Serine/threonine-specific protein kinase CTGF Connective tissue growth factor ALCL Anaplastic large cell lymphoma CXCL8 C-X-C motif chemokine 8 ALT Alanine aminotransferase DASA-58 Dihydro benzodioxin sulfonyl hexahydro AMPK 5' AMP-activated protein kinase diazepin sulfonyl benzenamine ANGPTL4 Angiopoietin-like 4 EGF Epidermal growth factor AP-1 Activator protein 1 EMT Epithelial–mesenchymal transition C/EBPβ CCAAT-enhancer binding protein β ErbB3 Erb-B2 Receptor tyrosine kinase 3 ERK-5 Extracellular-signal-regulated kinase 5 Mohd Rihan and Lakshmi Vineela Nalla has equal contribution for first FBP Fructose bisphosphate author. FGF Fibroblast growth factor FGFR1 Fibroblast growth factor receptor 1 * Amit KhairnarShard GAPDH Glyceraldehyde 3-phosphate dehydrogenase [email protected]@niperahm.ac.in; [email protected] GLUT-1 Glucose transporter -1 * Amit ShardKhairnar [email protected];@niperahm.ac.in [email protected] HCT-116 Human colon cancer cell line HIF-1α Hypoxia induced factor-1 alpha 1 Department of Pharmacology and Toxicology, National Institute of HK-2 Hexokinase-2 Pharmaceutical Education and Research (NIPER), Ahmedabad, HMGB1 High mobility group box-1 Palaj, Gandhinagar, Gujarat -382355, India IFN-ϒ Interferon-gamma 2 Department of Biotechnology, National Institute of Pharmaceutical IL-10 Interleukin-10 Education and Research (NIPER), Ahmedabad, Gujarat, India IL-13 Interleukin-13 3 Department of Medicinal Chemistry, National Institute of IL-1β Interleukin-1β Pharmaceutical Education and Research (NIPER), Ahmedabad, IL-4 Interleukin-4 Palaj, Gandhinagar, Gujarat -382355, India 150 Rihan M. et al. IL-6 Interleukin-6 Introduction JAK Janus kinase JNK c-Jun N-terminal kinases Cancer, a dynamic disease which develops one in three people LDH Lactate dehydrogenase during lifetime and considered as a major health burden to the LDH-A Lactate dehydrogenase-A society across the worldwide. According to the National LOX Lysyl oxidase Cancer Institute (NIH), roughly 1.7 million new cases will LPS Lipopolysaccharide be identified and 0.6 million people will perish with cancer MAPK Mitogen-activated protein kinases in the USA [1]. Typically, throughout the progression of a MAP K-5 Mitogen activated protein kinase-5 disease, cancers become more variant due to their somatic MCT-1 Monocarboxylase transporter -1 evolutionary changes [2] and this is referred as tumor hetero- MCT4 Monocarboxylate transporter 4 geneity which was explained by a pathologist, Rudolf MDM2 Mouse double minute-2 homolog Virchow in 1800s [3]. Moreover, it has been considered as a miRNA- MicroRNA-124 key element for the failure of classical and modern therapeu- 124 tics and offers multiple hindrances like chemotherapeutic re- MMP Matrix metalloproteinase sistance [4] cancer pharmacogenomics [5] and development MMP-2 Matrix metalloproteinase 2 of cancer stem-like cells [6]. It means the tumor shows the mTOR Mechanistic target of rapamycin existence of divergent tumors cells in terms of genetic and NF-kB Nuclear factor kappa B phenotypic patterns within the subpopulations of same histo- NK cells Natural killer cells pathological types of cancer in different patients or within OXPHOS Oxidative phosphorylation tumors that show divergent biological behavior and metastatic p53 Tumor protein p53 potential [7, 8]. This heterogeneity may be spatial and tempo- PD-1 Programmed cell death-1 ral in which former describes the uneven distribution of can- PD-4 Programmed cell death-4 cers subclones in various sites of primary tumors due to ge- PDGF Platelet-derived growth factor netic instability whereas the latter describes the variation in PDGF-BB Ligand for platelet derived growth factor molecular markers expression in same sites of tumors over a receptor period of time [9]. However, a new perspective of heteroge- PGAM1 Phosphoglycerate Mutase 1 neity has been explained recently based on the metabolic de- PGE2 Prostaglandin E2 mands of cancer cells termed as metabolic heterogeneity [10]. PI3K Phosphoinositide-3-kinase Clinical studies of various cancers like breast cancer, acute PIN1 Peptidyl-prolyl cis-trans isomerase myeloid leukemia, and Barrett's esophagus showed a positive PTP1B Tyrosine-protein phosphatase non-receptor correlation with tumors heterogeneity and displayed a high type 1 risk for cancer progression [11–13]. Four inter-dependent ROS Reactive oxygen species drivers like epigenetic regulation, cellular differentiation hier- RT-PCR Real time-polymerase chain reaction archies, gene expression stochasticity, and microenvironment SAICAR Succino 5-amino-4-imidazole-N- have direct control of cancer cells resulting in the tumor het- succinocarboxamide ribonucleotide erogeneity [14]. Many researchers found a high spatial and SDF-1 Stromal cell-derived factor 1 metabolic heterogeneity under different microenvironments shRNA Small hairpin ribonucleic acid such as developing more vascularate in the hypoxic region siRNA Small interfering ribonucleic acid [15], aberrant expression of glycolytic enzymes [16], lactate SOD2 Superoxide dismutase 2 mediated acidification [17], and autonomous cell proliferation STAT3 Signal transducer and activator of transcription 3 without stimuli [18]. Consequently, these relationships be- TCA Tricarboxylic acid tween cancer cells with its microenvironment might contribute TCR T cell receptor the cancers cells to adopt various conditions existed within the TEPP-46 Thieno-pyrrole-pyridazine tumor niche [19]. TGFα Transforming growth factor alpha Despite these heterogeneities, cancer cells even display TGFβ Transforming growth factor beta some basic analogous characteristics of various cancers which TH-1 T helper cell-1 are often described as Bhallmarks of cancer^ required for their TIMP Tissue inhibitor of metalloproteinases growth and multiplication [20]. Amongst all, dysregulated TNF-α Tumor necrosis factor-alpha cellular energetics has a starring role in supporting the tumor TRAF-5 TNF-receptor associated factor-5 development by providing the desired necessities to the cells US28 G-protein coupled receptor homolog US28 for fulfilling their metabolic demands by increasing aerobic VEGF Vascular endothelial growth factor glycolysis. This fulfillment gets accomplished by modifying vGPCR Viral G protein-coupled receptor the crucial metabolic enzymes (Hexokinase II, PKM2, LDH- Pyruvate Kinase M2: a Metabolic Bug in Re-Wiring the Tumor Microenvironment 151 A, and enolase, etc.) [21, 22], transporters (GLUT1, MCT-1, displayed the involvement of transporter (GLUT1) in the drug and MCT-4 etc.) [23] involved in different biosynthetic path- resistance of EGFR inhibitors (Gefitinib and Erlotinib) by ways through various oncogenic stimuli (HIF-1α,c-Myc, increasing the glucose metabolism in lung cancer suggesting PI3K/mTOR signaling) [24, 25]. Amongst all, PKM2 has a that glucose uptake by GLUT1 is a critical factor for the major role in shifting the tumor towards the aerobic glycolysis EGFR resistance [34]. Even the enzymes entailed with this and even remodels the tumor microenvironment (TME) cells process are upregulated and are modified post-translationally towards the tumor development, invasion, and metastasis. [35–37] by which the intermediates of the pathway like Lately, the studies on cancer cell metabolism greatly expanded glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), the understanding of cancer pathology and even revealed the glyceraldehyde-3-phosphate (G3P), dihydroxyacetone phos- presence of a widespread metabolic heterogeneity in tumors phate (DHAP) are fluxed for the biosynthesis of various mac- compared to spatial and temporal heterogeneities [10]. This romolecules (nucleic acids,
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