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Identification of DDX5 as a Potential Therapeutic Target of Osteosarcoma Using Thiazolone Probes
Donghui Sun1, Li Kang2, Xuwen Chen1
1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
Abstract:
Osteosarcoma (OS) is a rare malignant tumor that has predominantly affected children and adolescents in the past 50 years. The genomes of OS tumors exhibit a high degree of complexity, which leads to the great challenge of target identification for anti-OS. To date, no efficient therapeutic target for the treatment of OS has been validated in clinical practice. In our previous drug hunting for the treatment of OS by phenotypic screening, we found that thiazolone derivate (R)-8i was an effective and selective inhibitor against OS in MNNG/HOS cells and in vivo. However, the mechanism of action and specific molecular targets of (R)-8i remain unclear. In this study, we design and synthesize the photo-cross-linking probes based on the lead compound (R)-8i and identify DDX5 as a potential target protein using an activity-based protein profiling strategy. Further experiments including Western blot, shRNA knockdown experiments, cell colony formation, wound healing assays, and cellular thermal shift assays support that (R)-8i binds to DDX5 and induces its degradation, which affect cell proliferation and migration through the PI3K-AKT-mTOR signaling pathway. The research shows that DDX5 is a potential therapeutic target for the treatment of OS.
Insights
Researchers identified DDX5 as a potential therapeutic target for osteosarcoma (OS). A compound called (R)-8i targets DDX5, inhibiting OS cell proliferation and migration via the PI3K-AKT-mTOR pathway.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Osteosarcoma (OS) is a complex pediatric cancer with limited therapeutic targets.
- Current treatments for OS lack sufficient efficacy due to tumor complexity.
- Identifying novel therapeutic targets is crucial for advancing OS treatment.
Purpose of the Study:
- To elucidate the molecular mechanism and identify the target of the novel osteosarcoma inhibitor (R)-8i.
- To validate DDX5 as a potential therapeutic target for osteosarcoma treatment.
Main Methods:
- Synthesis of photo-cross-linking probes based on (R)-8i.
- Activity-based protein profiling to identify target proteins.
- Western blot, shRNA knockdown, colony formation, wound healing, and cellular thermal shift assays.
- Investigation of the PI3K-AKT-mTOR signaling pathway.
Main Results:
- DDX5 was identified as a potential molecular target of (R)-8i.
- (R)-8i binds to DDX5 and induces its degradation.
- DDX5 inhibition affects OS cell proliferation and migration.
- The PI3K-AKT-mTOR signaling pathway is implicated in (R)-8i's mechanism of action.
Conclusions:
- DDX5 is a promising therapeutic target for osteosarcoma.
- (R)-8i demonstrates potential as an anti-osteosarcoma agent by targeting DDX5.
- Targeting DDX5 offers a novel therapeutic strategy for osteosarcoma treatment.
