1. DNA-PKcs plays role in cancer metastasis through regulation of secreted proteins involved in migration and invasion
- Author
-
Ewa Kotula, Anthony Simon, Simon Saule, Marie Dutreix, Florent Dingli, Marie-Christine Lienafa, Vonick Sibut, Céline Agrario, Damarys Loew, and Nathalie Berthault
- Subjects
DNA damage ,Angiogenesis ,Mice, Nude ,CHO Cells ,DNA-Activated Protein Kinase ,Biology ,Matrix metalloproteinase ,Metastasis ,Mice ,Cricetulus ,Cell Movement ,Tandem Mass Spectrometry ,Cricetinae ,Neoplasms ,Report ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Gene Silencing ,Neoplasm Metastasis ,RNA, Small Interfering ,Molecular Biology ,Melanoma ,DNA-PKcs ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,Tumor microenvironment ,Nuclear Proteins ,Cell Biology ,medicine.disease ,Isogenic human disease models ,Gene Expression Regulation, Neoplastic ,enzymes and coenzymes (carbohydrates) ,Culture Media, Conditioned ,Cancer research ,Lymph Nodes ,biological phenomena, cell phenomena, and immunity ,Neoplasm Transplantation ,Developmental Biology ,DNA Damage - 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, MMP8, 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.
- Published
- 2015
- Full Text
- View/download PDF