Focal adhesion kinase-promoted tumor glucose metabolism is associated with a shift of mitochondrial respiration to glycolysis

• Published in: Oncogene Vol. 35; no. 15; pp. 1926 - 1942
• Main Authors: Zhang, J, Gao, Q, Zhou, Y, Dier, U, Hempel, N, Hochwald, S N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-04-2016; Nature Publishing Group
• Subjects: 101/6; 13/106; 13/109; 13/51; 13/89; 13/95; 42/70; 631/67/2327; 82/29; Apoptosis; Cancer; Carbon 13; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Care and treatment; Cell Adhesion; Cell Biology; Cell Line, Tumor; Cell viability; Cells, Cultured; Development and progression; Electron transport chain; Electron Transport Complex I - metabolism; Epithelial Cells - metabolism; Focal adhesion kinase; Focal Adhesion Kinase 1 - genetics; Focal Adhesion Kinase 1 - physiology; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Glucose; Glucose - metabolism; Glucose Transporter Type 1 - biosynthesis; Glucose Transporter Type 1 - genetics; Glycolysis; Growth factors; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; L-Lactate dehydrogenase; Lactates - metabolism; Lactic acid; Medicine; Medicine & Public Health; Metabolism; Mitochondria; Mitochondria - physiology; NADH-ubiquinone oxidoreductase; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Oncology; original-article; Oxidative Phosphorylation; Pancreas; Pancreatic cancer; Pancreatic Ducts - cytology; Pancreatic Ducts - metabolism; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Phenotypes; Phosphopyruvate hydratase; Phosphorylation; Phosphotransferases; Phosphotyrosine - metabolism; Properties; Protein kinases; Protein Processing, Post-Translational; Protein Structure, Tertiary; Proteins; Pyruvate kinase; Pyruvic acid; Recombinant Fusion Proteins - metabolism; Respiration; RNA Interference; RNA, Small Interfering - genetics; Solid tumors; Transfection; Tumorigenesis; Tumors; Tyrosine; Xenografts; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.256

Cancer cells often gains a growth advantage by taking up glucose at a high rate and undergoing aerobic glycolysis through intrinsic cellular factors that reprogram glucose metabolism. Focal adhesion kinase (FAK), a key transmitter of growth factor and anchorage stimulation, is aberrantly overexpressed or activated in most solid tumors, including pancreatic ductal adenocarcinomas (PDACs). We determined whether FAK can act as an intrinsic driver to promote aerobic glycolysis and tumorigenesis. FAK inhibition decreases and overexpression increases intracellular glucose levels during unfavorable conditions, including growth factor deficiency and cell detachment. Amplex glucose assay, fluorescence and carbon-13 tracing studies demonstrate that FAK promotes glucose consumption and glucose-to-lactate conversion. Extracellular flux analysis indicates that FAK enhances glycolysis and decreases mitochondrial respiration. FAK increases key glycolytic proteins, including enolase, pyruvate kinase M2 (PKM2), lactate dehydrogenase and monocarboxylate transporter. Furthermore, active/tyrosine-phosphorylated FAK directly binds to PKM2 and promotes PKM2-mediated glycolysis. On the other hand, FAK-decreased levels of mitochondrial complex I can result in reduced oxidative phosphorylation (OXPHOS). Attenuation of FAK-enhanced glycolysis re-sensitizes cancer cells to growth factor withdrawal, decreases cell viability and reduces growth of tumor xenografts. These observations, for the first time, establish a vital role of FAK in cancer glucose metabolism through alterations in the OXPHOS-to-glycolysis balance. Broadly targeting the common phenotype of aerobic glycolysis and more specifically FAK-reprogrammed glucose metabolism will disrupt the bioenergetic and biosynthetic supply for uncontrolled growth of tumors, particularly glycolytic PDAC.