Abstract
The proteasome inhibitor bortezomib is the most successfully applied chemotherapeutic drug for treating multiple myeloma. However, its clinical efficacy reduced due to resistance development. The underlying molecular mechanisms of bortezomib resistance are poorly understood. In this study, by combining in silico analysis and sgRNA library based drug resistance screening assay, we identified SENP2 (Sentrin/SUMO-specific proteases-2) as a bortezomib sensitive gene and found its expression highly downregulated in bortezomib resistant multiple myeloma patient’s samples. Furthermore, down regulation of SENP2 in multiple myeloma cell line RPMI8226 alleviated bortezomib induced cell proliferation inhibition and apoptosis, whereas, overexpression of SENP2 sensitized these cells to bortezomib treatment. We further demonstrate that knockdown of SENP2 in RPMI8226 cells increased SUMO2 conjugated IκBα that resulted in the activation of NF-κB. Taken together, we report that silencing of SENP2 and consequent activation of NF-κB through the modulation of IκBα sumoylation as a novel mechanism inducing bortezomib resistance in multiple myeloma.
Highlights
Multiple myeloma (MM) is a malignant plasma cell tumor that account for 12% of blood malignant tumors, which is the second most commonly diagnosed hematologic malignancy[1]
To uncover the molecular mechanisms contributing to the development of bortezomib resistance in MM, we aimed at identifying the genes whose loss of expression in MM may lead to bortezomib resistance development
Among the down regulated genes, we found SENP2 expression was highly down regulated in MM patients compared to healthy donors (Fig. 1A)
Summary
Multiple myeloma (MM) is a malignant plasma cell tumor that account for 12% of blood malignant tumors, which is the second most commonly diagnosed hematologic malignancy[1]. Despite applying multiple therapeutic drugs such as, proteasome inhibitor bortezomib[2] and immunomodulator thalidomide[3], the median MM patient survival was only slightly improved from 3–5 years to 5–7 years[4]. Sumoylation plays a crucial role in various cellular processes such as gene regulation, genome stability, DNA damage response, protein trafficking, signal transduction and cell cycle control[18,19,20]. We combined in silico analysis and bortezomib drug resistant screening assay to identify the genes, which contribute to the development of bortezomib resistance in MM. We show that loss of SENP2 expression potentiates bortezomib resistance development by activating NF-κB through the modulation of IκBα sumoylation
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