DNA-PKcs Plays Role in Cancer Metastasis Through Regulation of Secreted Proteins Involved in Migration and Invasion

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2015 May 29

PMID 26017556

Citations 27

Authors

Ewa Kotula

Nathalie Berthault

Celine Agrario

Marie-Christine Lienafa

Anthony Simon

Florent Dingli

Damarys Loew

Vonick Sibut

Simon Saule

Marie Dutreix

Affiliations

Soon will be listed here.

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.

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