Abstract
Unconventional prefoldin RPB5 interactor (URI), which acts as an oncoprotein in solid tumors, is associated with RNA polymerase II subunit 5. However, its impact on multiple myeloma (MM) has not been determined. We demonstrate here that URI is overexpressed in MM compared with plasma cells derived from healthy volunteers. Side population (SP) cells sorted from MM cells showed a much higher level of URI than non-SP cells. Using lentivirus-delivered shRNA, we established stable URI knockdown MM cell lines. URI inhibition significantly attenuated the proliferation of MM cells and decreased colony formation compared with the control cells. Tumor growth assays in NOD/SCID mice further confirmed the promotion role of URI during MM development in vivo. Furthermore, URI knockdown markedly reduced the abundance of SP in MM cell lines and enhanced the chemotherapeutic sensitivity of MM towards bortezomib. Mechanically, URI appears to be critically involved in modulating STAT3 activity through regulating interleukin (IL)-6 transcription via interaction with NFκBp65. In conclusion, URI may have an important role in the development of MM and chemotherapeutic resistance through activating the IL-6/STAT3 pathway.
Highlights
The growth and survival of MM cells is highly dependent upon the presence of certain growth-promoting cytokines in the bone marrow microenvironment
We investigated the expression levels of Unconventional prefoldin RPB5 interactor (URI) in MM and normal plasma cells separated from bone marrow
URI protein levels were upregulated substantially in MM cells from almost all patients with MM (20/22), whereas the normal plasma cells contained a very low level of URI (Figure 1e). These results demonstrate that URI is overexpressed in MM cells from MM patients compared with normal plasma cells
Summary
The growth and survival of MM cells is highly dependent upon the presence of certain growth-promoting cytokines in the bone marrow microenvironment. Whereas the main producers of IL-6 in the bone marrow microenvironment are most likely the bone marrow stromal cells, some MM cell lines both produce and respond to IL-6, supporting an autocrine proliferation loop.[10,13,14,15] Importantly, autocrine IL-6 production was shown to be associated with a highly malignant phenotype, a high proliferative index, and resistance to drug-induced apoptosis.[15] In addition, serum. We determined the effect of URI in MM on cell proliferation, chemotherapy resistance, survival in vitro, and growth in vivo
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