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Published on: January 31, 2018
DUSP6 regulates drug sensitivity by modulating DNA damage response
T V Bagnyukova1, D Restifo, N Beeharry
1Program in Developmental Therapeutics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
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.
Insights
Dual specificity phosphatase 6 (DUSP6) depletion reduces cancer cell viability and enhances chemotherapy effectiveness. This study reveals DUSP6’s role in DNA damage response, impacting genomic integrity and cancer treatment sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Dual specificity phosphatase 6 (DUSP6) is a mitogen-activated protein kinase phosphatase regulating ERK1/2 activity.
- DUSP6 expression is altered in cancer and other pathological conditions.
Purpose of the Study:
- To investigate the role of DUSP6 in cancer cell viability and response to therapy.
- To elucidate the mechanisms by which DUSP6 influences DNA damage response (DDR).
Main Methods:
- Cancer cell lines were depleted of DUSP6 using siRNA and shRNA.
- Sensitivity to targeted inhibitors and chemotherapeutic agents was assessed in vitro and in vivo.
- Proteomic analysis identified downstream signaling pathways and DNA damage response markers.
Main Results:
- DUSP6 depletion reduced cancer cell viability and increased sensitivity to EGFR inhibitors and cytotoxic agents.
- Inactivation of DUSP6 activated CHEK2 and p38 kinases within the DDR pathway.
- Elevated levels of phosphorylated H2AX, ATM, and CHEK2 confirmed DUSP6’s role in regulating DDR.
Conclusions:
- DUSP6 plays a significant role in maintaining genomic integrity in cancer cells.
- Targeting DUSP6 may enhance the efficacy of chemotherapy and targeted therapies in cancer treatment.
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