title: Glycolysis is the primary bioenergetic pathway for cell motility and cytoskeletal remodeling in human prostate and breast cancer cells.
abstract: The ability of a cancer cell to detach from the primary tumor and move to distant sites is fundamental to a lethal cancer phenotype. Metabolic transformations are associated with highly motile aggressive cellular phenotypes in tumor progression. Here, we report that cancer cell motility requires increased utilization of the glycolytic pathway. Mesenchymal cancer cells exhibited higher aerobic glycolysis compared to epithelial cancer cells while no significant change was observed in mitochondrial ATP production rate. Higher glycolysis was associated with increased rates of cytoskeletal remodeling, greater cell traction forces and faster cell migration, all of which were blocked by inhibition of glycolysis, but not by inhibition of mitochondrial ATP synthesis. Thus, our results demonstrate that cancer cell motility and cytoskeleton rearrangement is energetically dependent on aerobic glycolysis and not oxidative phosphorylation. Mitochondrial derived ATP is insufficient to compensate for inhibition of the glycolytic pathway with regard to cellular motility and CSK rearrangement, implying that localization of ATP derived from glycolytic enzymes near sites of active CSK rearrangement is more important for cell motility than total cellular ATP production rate. These results extend our understanding of cancer cell metabolism, potentially providing a target metabolic pathway associated with aggressive disease.
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Takumi
authors.initials: T
authors.lastname: Shiraishi
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Verdone
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pathology, Division of Neuropathology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Ulf D
authors.initials: UD
authors.lastname: Kahlert
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Hernandez
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Torga
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jelani C
authors.initials: JC
authors.lastname: Zarif
authors.affiliation: Department of Integrative Mathematical Oncology and Department of Diagnostic Imaging, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Tamir
authors.initials: T
authors.lastname: Epstein
authors.affiliation: Department of Integrative Mathematical Oncology and Department of Diagnostic Imaging, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Gatenby
authors.affiliation: The Wilmer Eye Institute and Department of Biomedical Engineering, Baltimore, MD, USA.
authors.forename: Annemarie
authors.initials: A
authors.lastname: McCartney
authors.affiliation: The Wilmer Eye Institute and Department of Biomedical Engineering, Baltimore, MD, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Elisseeff
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Mooney
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. In Vivo Cellular and Molecular Imaging Center, The Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: An
authors.affiliation: Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA. Department of Oncology, Johns Hopkins University, Baltimore, MD, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000332:Aerobiosis; D001943:Breast Neoplasms / Q000378:metabolism*; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008858:Microscopy, Phase-Contrast; D008928:Mitochondria / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000737:chemistry; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D000255:Adenosine Triphosphate; D010100:Oxygen