DUSP6 regulates drug sensitivity by modulating DNA damage response.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

Our results provide a novel insight into the DUSP6 function in regulating genomic integrity and sensitivity to chemotherapy in cancer.

• Authors: T V Bagnyukova, D Restifo, N Beeharry, L Gabitova, T Li, I G Serebriiskii, E A Golemis, I Astsaturov
• Journal: British journal of cancer (Br J Cancer) Vol. 109 Issue 4 Pg. 1063-71 (Aug 20 2013) ISSN: 1532-1827 [Electronic] England
• PMID: 23839489 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Checkpoint Kinase 2
• ErbB Receptors
• CHEK2 protein, human
• Chek2 protein, mouse
• Protein Serine-Threonine Kinases
• p38 Mitogen-Activated Protein Kinases
• Dual Specificity Phosphatase 6

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Checkpoint Kinase 2
• DNA Damage (drug effects)
• Dual Specificity Phosphatase 6 (physiology)
• ErbB Receptors (antagonists & inhibitors)
• HEK293 Cells
• Humans
• In Situ Nick-End Labeling
• MAP Kinase Signaling System (physiology)
• Mice
• Mice, SCID
• Phosphorylation
• Protein Serine-Threonine Kinases (drug effects, metabolism)
• Proteomics
• Signal Transduction
• Xenograft Model Antitumor Assays
• p38 Mitogen-Activated Protein Kinases (drug effects, metabolism)