title: DNA-PKcs plays role in cancer metastasis through regulation of secreted proteins involved in migration and invasion.
abstract: The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a major role in DNA damage signaling and repair and is also frequently overexpressed in tumor metastasis. We used isogenic cell lines expressing different levels of DNA-PKcs to investigate the role of DNA-PKcs in metastatic development. We found that DNA-PKcs participates in melanoma primary tumor and metastasis development by stimulating angiogenesis, migration and invasion. Comparison of conditioned medium content from DNA-PKcs-proficient and deficient cells reveals that DNA-PKcs controls secretion of at least 103 proteins (including 44 metastasis-associated with FBLN1, SERPINA3, MMP-8, HSPG2 and the inhibitors of matrix metalloproteinases, such as α-2M and TIMP-2). High throughput analysis of secretomes, proteomes and transcriptomes, indicate that DNA-PKcs regulates the secretion of 85 proteins without affecting their gene expression. Our data demonstrate that DNA-PKcs has a pro-metastatic activity via the modification of the tumor microenvironment. This study shows for the first time a direct link between DNA damage repair and cancer metastasis and highlights the importance of DNA-PKcs as a potential target for anti-metastatic treatment.
authors.affiliation: a Centre National de Recherche Scientifique (CNRS) UMR3347; Institut National de la Santé et de Recherche Médicale (INSERM) U1021; Institut Curie ; Orsay , France.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kotula
authors.forename: Nathalie
authors.initials: N
authors.lastname: Berthault
authors.forename: Celine
authors.initials: C
authors.lastname: Agrario
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Lienafa
authors.forename: Anthony
authors.initials: A
authors.lastname: Simon
authors.forename: Florent
authors.initials: F
authors.lastname: Dingli
authors.forename: Damarys
authors.initials: D
authors.lastname: Loew
authors.forename: Vonick
authors.initials: V
authors.lastname: Sibut
authors.forename: Simon
authors.initials: S
authors.lastname: Saule
authors.forename: Marie
authors.initials: M
authors.lastname: Dutreix
mesh_terms: D000818:Animals; D016466:CHO Cells; D002465:Cell Movement; D049109:Cell Proliferation; D006224:Cricetinae; D003412:Cricetulus; D017077:Culture Media, Conditioned; D004249:DNA Damage; D051747:DNA-Activated Protein Kinase / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D017077:Culture Media, Conditioned; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human
keywords: CM, conditioned media; DNA damage; DNA-PK; DNA-PK, DNA-dependent protein kinase; DNA-PKcs, DNA-PK catalytic subunit; DSB, double-strand break; ECM, extracellular matrix; MMP inhibition; MMP, matrix metalloproteinase; MS, mass spectrometry; NHEJ, non-homologous end joining; SILAC, stable isotope labeling by amino acids in cell culture; TIMP, tissue inhibitor of metalloproteinase.; metastasis; secretion; α-2M, α-2-macroglobulin