Abstract
The introduction of novel frontline agents in multiple myeloma (MM), like immunomodulatory drugs and proteasome inhibitors, has improved the overall survival of patients. Yet, MM is still not curable, and drug resistance (DR) remains the main challenge. To improve the understanding of DR in MM, we established a resistant cell line (MOLP8/R). The exploration of DR mechanisms yielded an overexpression of HIF1α, due to impaired proteasome activity of MOLP8/R. We show that MOLP8/R, like other tumor cells, overexpressing HIF1α, have an increased resistance to the immune system. By exploring the main target genes regulated by HIF1α, we could not show an overexpression of these targets in MOLP8/R. We, however, show that MOLP8/R cells display a very high overexpression of LCP1 gene (l-Plastin) controlled by HIF1α, and that this overexpression also exists in MM patient samples. The l-Plastin activity is controlled by its phosphorylation in Ser5. We further show that the inhibition of l-Plastin phosphorylation restores the sensitivity of MOLP8/R to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Our results reveal a new target gene of DR, controlled by HIF1α.
Highlights
Multiple myeloma (MM) is a malignant disorder involving uncontrolled proliferation of plasma cells within the bone marrow [1]
We set up a resistant cell line to doxorubicin (DOX) from MM cell line, MOLP8. We demonstrate that this cell line is resistant to pomalidomide and carfilzomib, the latest IMiD and proteasome inhibitors (PIs) validated by the FDA (Food and Drugs Administration), but it is sensitive to dexamethasone, whereas the MOLP8 cell line is resistant to this drug
We demonstrate that the inhibition of L-Plastin phosphorylation leads to sensitivity of MOLP8/R to PIs and Pomalidomide
Summary
Multiple myeloma (MM) is a malignant disorder involving uncontrolled proliferation of plasma cells within the bone marrow [1]. The development of MM is localized in the bone marrow, constituting the microenvironment which participates intimately in the progression of the disease, cell proliferation, angiogenesis, metastasis, and drug resistance [7,14,15]. In order to adapt to hypoxia, HIF1α activates target genes having a hypoxia responsive element (HRE) upstream of their promoters [22] These HIF1α-regulated genes promote tumor progression, metastasis, and drug resistance [23,24,25]. The study highlights a new HIF1α-regulated gene in MOLP8/R cells, namely LCP1 This protein, L-Plastin, activated by its phosphorylation in Ser, is overexpressed in our resistant clone. We identified a new protein regulated by HIF1α, and involved in MDR of MM, which can be a potential target to overcome drug resistance in MM
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