title: Focal adhesion kinase-promoted tumor glucose metabolism is associated with a shift of mitochondrial respiration to glycolysis.
abstract: 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.
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Nanobioscience Constellation, SUNY College of Nanoscale Science and Engineering, Albany, NY, USA.
authors.forename: U
authors.initials: U
authors.lastname: Dier
authors.affiliation: Nanobioscience Constellation, SUNY College of Nanoscale Science and Engineering, Albany, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hempel
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Hochwald
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D042967:Electron Transport Complex I / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis / Q000235:genetics; D006019:Glycolysis; D006801:Humans; D007773:Lactates / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D010085:Oxidative Phosphorylation; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D051272:Glucose Transporter Type 1; D007773:Lactates; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C495677:SLC2A1 protein, human; D019000:Phosphotyrosine; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D042967:Electron Transport Complex I; D005947:Glucose