DUSP6 regulates drug sensitivity by modulating DNA damage response
Authors:
- D RestifoDRD Restifo
- N BeeharryNBN Beeharry
- L GabitovaLGL Gabitova
- T LiTLT Li
- I G SerebriiskiiISI G Serebriiskii
- E A GolemisEGE A Golemis
- I AstsaturovIAI Astsaturov
Open Access
- 9 July 2013
- journal article
- Published by Springer Nature in British Journal of Cancer
- Vol. 109 (4) , 1063-1071
Abstract
Dual specificity phosphatase 6 (DUSP6) is a member of a family of mitogen-activated protein kinase phosphatases that dephosphorylates and inhibits activated ERK1/2. Dual specificity phosphatase 6 is dynamically regulated in developmental and pathological conditions such as cancer. Cancer cell lines were made deficient in DUSP6 by siRNA and shRNA silencing. Sensitivity to anti-EGFR and chemotherapeutic agents was determined in viability and apoptosis assays, and in xenografts established in SCID mice. Cellular effects of DUSP6 inactivation were analysed by proteomic methods, followed by analysis of markers of DNA damage response (DDR) and cell cycle. We determined that depletion of DUSP6 reduced the viability of cancer cell lines and increased the cytotoxicity of EGFR and other targeted inhibitors, and cytotoxic agents, in vitro and in vivo. Subsequent phosphoproteomic analysis indicated DUSP6 depletion significantly activated CHEK2 and p38, which function in the DDR pathway, and elevated levels of phosphorylated H2AX, ATM, and CHEK2, for the first time identifying a role for DUSP6 in regulating DDR. Our results provide a novel insight into the DUSP6 function in regulating genomic integrity and sensitivity to chemotherapy in cancer.Keywords
This publication has 36 references indexed in Scilit:
- Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivityNature Biotechnology, 2011
- Functional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphomaNature Communications, 2011
- Mitogen-activated Protein Kinase (MAPK) Phosphatase 3-mediated Cross-talk between MAPKs ERK2 and p38αJournal of Biological Chemistry, 2011
- Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modificationsGenes & Development, 2011
- Synthetic Lethal Screen of an EGFR-Centered Network to Improve Targeted TherapiesScience Signaling, 2010
- Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cellsCarcinogenesis, 2010
- MEK1 mutations confer resistance to MEK and B-RAF inhibitionProceedings of the National Academy of Sciences, 2009
- Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor CellsScience, 2009
- Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2Current Opinion in Cell Biology, 2009
- p53-Deficient Cells Rely on ATM- and ATR-Mediated Checkpoint Signaling through the p38MAPK/MK2 Pathway for Survival after DNA DamageCancer Cell, 2007