title: PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.
abstract: Cancer cells can divert metabolites into anabolic pathways to support their rapid proliferation and to accumulate the cellular building blocks required for tumour growth. However, the specific bioenergetic profile of invasive and metastatic cancer cells is unknown. Here we report that migratory/invasive cancer cells specifically favour mitochondrial respiration and increased ATP production. Invasive cancer cells use the transcription coactivator peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A, also known as PGC-1α) to enhance oxidative phosphorylation, mitochondrial biogenesis and the oxygen consumption rate. Clinical analysis of human invasive breast cancers revealed a strong correlation between PGC-1α expression in invasive cancer cells and the formation of distant metastases. Silencing of PGC-1α in cancer cells suspended their invasive potential and attenuated metastasis without affecting proliferation, primary tumour growth or the epithelial-to-mesenchymal program. Inherent genetics of cancer cells can determine the transcriptome framework associated with invasion and metastasis, and mitochondrial biogenesis and respiration induced by PGC-1α are also essential for functional motility of cancer cells and metastasis.
authors.affiliation: 1] Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA [2] Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: LeBleu
authors.affiliation: Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Joyce T
authors.initials: JT
authors.lastname: O'Connell
authors.affiliation: Department of Cell Biology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Karina N
authors.initials: KN
authors.lastname: Gonzalez Herrera
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52 D-20246 Hamburg, Germany.
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
authors.affiliation: Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52 D-20246 Hamburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.affiliation: Department of Cell Biology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, 01509-010, Sao Paulo, Brazil.
authors.forename: Fernanda Machado
authors.initials: FM
authors.lastname: de Carvalho
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, 01509-010, Sao Paulo, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: Damascena
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, 01509-010, Sao Paulo, Brazil.
authors.forename: Ludmilla Thome
authors.initials: LT
authors.lastname: Domingos Chinen
authors.affiliation: International Research Center, A. C. Camargo Cancer Center, 01509-010, Sao Paulo, Brazil.
authors.forename: Rafael M
authors.initials: RM
authors.lastname: Rocha
authors.affiliation: 1] Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: 1] Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA [2] Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors