Rolapitant treats lung cancer by targeting deubiquitinase OTUD3
Tongde Du1, Quan Gu1, Yonghui Zhang2
1Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
Background:
Lung cancer is cancer with the highest morbidity and mortality in the world and poses a serious threat to human health. Therefore, discovering new treatments is urgently needed to improve lung cancer prognosis. Small molecule inhibitors targeting the ubiquitin-proteasome system have achieved great success, in which deubiquitinase inhibitors have broad clinical applications. The deubiquitylase OTUD3 was reported to promote lung tumorigenesis by stabilizing oncoprotein GRP78, implying that inhibition of OTUD3 may be a therapeutic strategy for lung cancer.
Results:
In this study, we identified a small molecule inhibitor of OTUD3, Rolapitant, by computer-aided virtual screening and biological experimental verification from FDA-approved drugs library. Rolapitant inhibited the proliferation of lung cancer cells by inhibiting deubiquitinating activity of OTUD3. Quantitative proteomic profiling indicated that Rolapitant significantly upregulated the expression of death receptor 5 (DR5). Rolapitant also promoted lung cancer cell apoptosis through upregulating cell surface expression of DR5 and enhanced TRAIL-induced apoptosis. Mechanistically, Rolapitant directly targeted the OTUD3-GRP78 axis to trigger endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP)-DR5 signaling, sensitizing lung cancer cells to TRAIL-induced apoptosis. In the vivo assays, Rolapitant suppressed the growth of lung cancer xenografts in immunocompromised mice at suitable dosages without apparent toxicity.
Conclusion:
In summary, the present study identifies Rolapitant as a novel inhibitor of deubiquitinase OTUD3 and establishes that the OTUD3-GRP78 axis is a potential therapeutic target for lung cancer.
Insights
Rolapitant inhibits deubiquitinase OTUD3, a key factor in lung cancer progression. This drug promotes cancer cell death by targeting the OTUD3-GRP78 axis and upregulating death receptor 5, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Lung cancer remains a leading cause of global mortality, necessitating novel therapeutic interventions.
- Targeting the ubiquitin-proteasome system with small molecule inhibitors, particularly deubiquitinase inhibitors, shows promise for cancer treatment.
- The deubiquitylase OTUD3 promotes lung tumorigenesis by stabilizing oncoprotein GRP78, suggesting OTUD3 inhibition as a potential lung cancer therapy.
Purpose of the Study:
- To identify a small molecule inhibitor of OTUD3 from FDA-approved drugs.
- To investigate the therapeutic potential of OTUD3 inhibition in lung cancer.
- To elucidate the molecular mechanisms by which OTUD3 inhibition affects lung cancer cells.
Main Methods:
- Computer-aided virtual screening and experimental validation were used to identify OTUD3 inhibitors.
- Quantitative proteomic profiling was employed to analyze drug-induced molecular changes.
- In vitro cell proliferation and apoptosis assays, along with in vivo xenograft studies, were conducted.
Main Results:
- Rolapitant was identified as a novel small molecule inhibitor of OTUD3, suppressing lung cancer cell proliferation.
- Rolapitant upregulated death receptor 5 (DR5) expression, enhancing TRAIL-induced apoptosis.
- The drug triggered endoplasmic reticulum (ER) stress and CHOP-DR5 signaling via the OTUD3-GRP78 axis, sensitizing cells to apoptosis.
- In vivo, Rolapitant effectively suppressed lung cancer xenograft growth without significant toxicity.
Conclusions:
- Rolapitant is a novel inhibitor of the deubiquitinase OTUD3.
- The OTUD3-GRP78 axis represents a viable therapeutic target for lung cancer treatment.
- Rolapitant demonstrates potential as an anti-lung cancer drug by inducing apoptosis through ER stress and DR5 upregulation.
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