REVIEW ARTICLE Protein networks linking Warburg and reverse Warburg effects to cancer cell metabolism Dina Johar 1 | Ahmed O. Elmehrath 2 | Rania M. Khalil 3 | Mostafa H. Elberry 4 | Samy Zaky 5 | Samy A. Shalabi 6,7 | Larry H. Bernstein 8,9 1 Department of Biochemistry and Nutrition, Faculty of Women for Arts, Sciences and Education, Ain Shams University, Heliopolis, Cairo, Egypt 2 Faculty of Medicine, Cairo University, Cairo, Egypt 3 Department of Biochemistry, Pharmacy College, Delta University for Science and Technology, Gamasa, Egypt 4 Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt 5 Hepatogastroenterology and Infectious Diseases, Faculty of Medicine, Al-Azhar University, Cairo, Egypt 6 Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt 7 Consultant Pathologist, Kuwait, Kuwait 8 Emeritus Prof. Department of Pathology, Yale University, Connecticut, USA 9 Triplex Consulting Pharmaceuticals, 54 Firethorn Lane Northampton, MA 01060, USA Abstract It was 80 years after the Otto Warburg discovery of aerobic glycolysis, a major hallmark in the understanding of cancer. The Warburg effect is the preference of cancer cell for glycolysis that produces lactate even when sufficient oxygen is provided. “reverse Warburg effect” refers to the interstitial tissue communi- cations with adjacent epithelium, that in the process of carcinogenesis, is needed to be explored. Among these cell–cell communications, the contact between epithelial cells; between epithelial cells and matrix; and between fibroblasts and inflammatory cells in the underlying matrix. Cancer involves dysregulation of Warburg and reverse Warburg cellular metabolic pathways. How these gene and protein-based regulatory mechanisms have functioned has been the basis for this review. The importance of the Warburg in oxidative phosphorylation suppression, with increased glycolysis in cancer growth and proliferation is emphasized. Studies that are directed at pathways that would be expected to shift cell metabolism to an increased oxidation and to a decrease in glycolysis are emphasized. Key enzymes required for oxidative phosphoryla- tion, and affect the inhibition of fatty acid metabolism and glutamine depen- dence are conferred. The findings are of special interest to cancer pharmacotherapy. Studies described in this review are concerned with the Abbreviations: AMP, Adenosine monophosphate; AFR, ATP flux ratio; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; AICAR, 5-aminoimidazole-4-carboxamide-1-D-ribo-furanoside; KG, -ketoglutarate; AD, Alzheimer's disease; 3BP, 3-bromopyruvate; DNP, 2,4-dinitrophenol; B-HOB, β-hydroxybutyrate; CAV-1, caveolin-1; CBP, cAMP-response element-binding protein; CMA, chaperone-mediated autophagy; CD147, cluster of differentiation; CLL, chronic lymphocytic leukemia; CCOx, cytochrome c oxidase; COX II, cytochrome c oxidase subunit II; DBD, deaminase- binding domain; dbc-AMP, dibutyryl cyclic AMP; EMT, epithelial-mesenchymal transition; ERS, endoplasmic reticulum stress; EV, extracellular vesicle; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLS 1, glutaminase 1; GPCRs, G protein-coupled receptors; HK, hexokinase; FDG-PET, 18 fluoro-deoxyglucose-based positron emission tomography; FOXC2, forkhead box protein C2; FH, fumarate hydratase; GABA, γ-aminobutyric acid; IMM, inner mitochondrial membrane; IMS, intermembrane space; FeS, iron sulfate; ISC, iron–sulfur clusters; LDHA, lactate dehydrogenase A; LPS, lipopolysaccharide; mTORC1, mammalian target of rapamycin complex 1; mtDNA, mitochondrial DNA; MPC, mitochondrial pyruvate carrier; MAPKs, mitogen-activated protein kinases; mAbs, monoclonal antibodies; NPBac, nodal point of bifurcation anabolic and catabolic processes; OMM, outer mitochondrial membrane; NSCLC, non-small cell lung cancer; OXPHOS, oxidative phosphorylation; PFK, phosphofructokinase; PFK-1, phosphofructose-1-kinase; PFK2, phosphofructo-2 kinase; PGK-1, phosphoglycerate kinase 1; Pi, inorganic phosphate; PI3K, phosphoinositide 3-kinase; p-PKM2, phospho-pyruvate kinase M2; Kv, potassium channels; PC, pyruvate carboxylase; PK, pyruvate kinase; PKM1, pyruvate kinase M1; PKM2, pyruvate kinase M2 ; Rbx1, RING box protein 1; S1P, sphingosine 1-phosphate; SDH, succinate dehydrogenase; TCR, T-cell receptor; TEAD, TEA domain; TAMs, tumor-associated macrophages; Tyk2, Jak1, Jak2), Jak tyrosine kinases; UP1, uncoupling protein 1; UPR, unfolded protein response; YAP, yes association protein; TAZ, WW domain-containing transcription factor. Received: 4 May 2021 Accepted: 22 June 2021 DOI: 10.1002/biof.1768 BioFactors. 2021;1–16. wileyonlinelibrary.com/journal/biof © 2021 International Union of Biochemistry and Molecular Biology 1