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Targeting of SKP2 to combat drug resistance in multiple myeloma
Omar Faruq1,2, Jane Ngo1,2, Deepak Iyer1,2
1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Abstract:
Multiple myeloma (MM) is an incurable plasma cell malignancy in which drug resistance remains a significant limitation to treatment. SKP2, the substrate-recognition component of the SCF-SKP2 ubiquitin-protein ligase complex, plays a critical role in the progression of various cancers, including MM. Targeting SKP2 as a therapeutic strategy offers a promising avenue for combating drug resistance in myeloma. Here, we show that SKP2 expression increases as the disease progresses from pre-myeloma to newly diagnosed and relapsed stages. Gene set enrichment analysis (GSEA) and immunoblotting further revealed that SKP2 inhibition by the preclinical chemical inhibitor SkpinC1 leads to decreased STAT3 inflammatory signalling and c-MYC expression in myeloma cells. When tested in SKP2-overexpressing cells, SkpinC1 retained the ability to reduce activated STAT3, c-MYC, and c-MAF protein levels to impair cell growth and induce apoptosis. Furthermore, SkpinC1 synergistically enhanced the sensitivity of patient myeloma samples to bortezomib. Taken together, these findings underline the potential of SKP2 inhibition to overcome drug resistance in MM.
Insights
Targeting SKP2 with SkpinC1 shows promise for overcoming drug resistance in multiple myeloma (MM). This inhibition reduces key signaling pathways and enhances sensitivity to existing therapies like bortezomib.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Multiple myeloma (MM) is an incurable plasma cell cancer characterized by significant therapeutic drug resistance.
- SKP2, a key component of the SCF-SKP2 ubiquitin-protein ligase complex, is implicated in cancer progression and drug resistance in MM.
Purpose of the Study:
- To investigate the role of SKP2 in multiple myeloma progression and drug resistance.
- To evaluate the therapeutic potential of inhibiting SKP2 using the preclinical inhibitor SkpinC1 in MM.
Main Methods:
- Analysis of SKP2 expression across different stages of multiple myeloma.
- Utilizing gene set enrichment analysis (GSEA) and immunoblotting to assess the effects of SkpinC1.
- Testing SkpinC1 in SKP2-overexpressing MM cells and patient-derived samples.
Main Results:
- SKP2 expression was found to increase with disease progression in MM.
- SkpinC1 treatment led to decreased STAT3 signaling and c-MYC expression in MM cells.
- SkpinC1 reduced activated STAT3, c-MYC, and c-MAF levels, impairing cell growth and inducing apoptosis.
- SkpinC1 synergistically enhanced the efficacy of bortezomib in patient myeloma samples.
Conclusions:
- SKP2 inhibition represents a promising strategy to overcome drug resistance in multiple myeloma.
- Targeting SKP2 may restore sensitivity to conventional therapies and offer a new therapeutic avenue for MM patients.
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