p38 MAPK activation through B7-H3-mediated DUSP10 repression promotes chemoresistance
Karine Flem-Karlsen1,2, Christina Tekle1, Tove Øyjord1
1Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
Scientific Reports
|April 11, 2019
Summary
Inhibiting B7-H3 enhances melanoma cell sensitivity to chemotherapy drugs dacarbazine (DTIC) and cisplatin. This occurs via increased DUSP10 expression, which inactivates p38 MAPK, overcoming drug resistance.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- B7-H3 protein influences cancer's growth, metastasis, and drug resistance.
- Melanoma treatment faces challenges due to chemoresistance.
- Understanding B7-H3's role in drug resistance can improve melanoma therapies.
Purpose of the Study:
- To investigate how B7-H3 affects melanoma cell sensitivity to dacarbazine (DTIC) and cisplatin.
- To explore the molecular mechanisms underlying B7-H3-mediated chemoresistance.
Main Methods:
- Knockdown of B7-H3 expression in melanoma cells.
- Assessing in vitro and in vivo sensitivity to DTIC and cisplatin.
- Analyzing p38 MAPK phosphorylation and DUSP10 expression.
- Using siRNA to knock down DUSP10.
Main Results:
- B7-H3 knockdown increased melanoma cell sensitivity to DTIC and cisplatin.
- This correlated with decreased p38 MAPK phosphorylation.
- DUSP10 expression increased in B7-H3 knockdown cells.
- DUSP10 knockdown reversed the increased DTIC sensitivity.
Conclusions:
- B7-H3 inhibition enhances chemo-sensitivity in melanoma.
- Melanoma chemoresistance involves B7-H3, DUSP10, and p38 MAPK pathway.
- Combining chemotherapy with B7-H3 inhibition may be a viable therapeutic strategy.
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