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Published on: May 15, 2019
Novel reversible selective inhibitor of CRM1 for targeted therapy in ovarian cancer
Xuejiao Liu1,2, Yulong Chong2, Huize Liu2
1Blood Diseases Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China.
Background:
Ovarian cancer represents the most fatal type of gynecological malignancies. Unfortunately, there are still no effective targeted treatment strategies for ovarian cancer. Overexpression of CRM1 has been correlated with poor prognosis of patients with ovarian cancer.
Aim:
In this study, we investigated the antitumor effects of a novel reversible inhibitor of CRM1 in ovarian cancer cells.
Methods:
The effects of S109 on proliferation was detected by CCK-8, EdU, clonogenic assay. The protein expression were determined by Western blot. The subcellular localization of RanBP1 was analyzed by immunofluorescence microscopy assay.
Results:
We demonstrated that S109 could induce nuclear accumulation of RanBP1, a canonical biomarker for CRM1 inhibition. This effect was clearly reversible in the majority of the cells, whereas the inhibitory effect of LMB could not be reversed. Our data reveal that treatment with S109 results in decrease in proliferation and colonogenic capacity of ovarian cancer cells by arresting cell cycle. Mechanistically, S109 treatment increase the expression of the cyclin-dependent kinase inhibitor p21, while it reduced the expression of cell cycle promoting proteins, Cyclin D1 and Cyclin B. CRM1 level itself was also down-regulated following S109 treatment. Furthermore, the nuclei of cells incubated with S109 accumulated tumor suppressor proteins (Foxo1, p27 and IκB-α). More importantly, Cys528 mutation of CRM1 abolished the ability of S109 to block proliferation of ovarian cancer cells.
Conclusions:
Together, our study identifies CRM1 as a valid target in ovarian cancer and provides a basis for the development of S109 in ovarian cancer.
Insights
A novel CRM1 inhibitor, S109, effectively reduces ovarian cancer cell proliferation by arresting the cell cycle and downregulating CRM1. This reversible inhibitor shows promise for targeted ovarian cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Ovarian cancer is a highly fatal gynecological malignancy with limited targeted treatment options.
- Overexpression of CRM1 is linked to poor patient prognosis in ovarian cancer.
- Current therapeutic strategies for ovarian cancer remain largely ineffective.
Purpose of the Study:
- To investigate the antitumor effects of a novel reversible inhibitor of CRM1, named S109, in ovarian cancer cells.
- To evaluate S109 as a potential targeted therapy for ovarian cancer.
Main Methods:
- Cell proliferation was assessed using CCK-8, EdU, and clonogenic assays.
- Protein expression levels were determined via Western blot analysis.
- Subcellular localization of RanBP1 was analyzed using immunofluorescence microscopy.
Main Results:
- S109 induced reversible nuclear accumulation of RanBP1, a CRM1 inhibition biomarker.
- S109 treatment decreased ovarian cancer cell proliferation and colony formation by arresting the cell cycle.
- S109 increased p21 expression while decreasing Cyclin D1 and Cyclin B, and also downregulated CRM1 levels.
- Nuclear accumulation of tumor suppressor proteins (Foxo1, p27, IκB-α) was observed with S109 treatment.
- A Cys528 mutation in CRM1 rendered ovarian cancer cells resistant to S109's antiproliferative effects.
Conclusions:
- CRM1 is identified as a viable therapeutic target for ovarian cancer.
- S109 demonstrates significant antitumor activity and provides a foundation for its development as an ovarian cancer treatment.
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