URI regulates tumorigenicity and chemotherapeutic resistance of multiple myeloma by modulating IL-6 transcription.

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.

• Authors: J-L Fan, J Zhang, L-W Dong, W-J Fu, J Du, H-G Shi, H Jiang, F Ye, H Xi, C-Y Zhang, J Hou, H-Y Wang
• Journal: Cell death & disease (Cell Death Dis) Vol. 5 Pg. e1126 (Mar 13 2014) ISSN: 2041-4889 [Electronic] England
• PMID: 24625985 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Boronic Acids
• IL6 protein, human
• Interleukin-6
• Intracellular Signaling Peptides and Proteins
• Pyrazines
• RELA protein, human
• Repressor Proteins
• STAT3 Transcription Factor
• STAT3 protein, human
• Transcription Factor RelA
• URI1 protein, human
• Bortezomib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Boronic Acids (pharmacology)
• Bortezomib
• Case-Control Studies
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukin-6 (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Multiple Myeloma (drug therapy, genetics, metabolism, pathology)
• Neoplastic Stem Cells (drug effects, metabolism, pathology)
• Pyrazines (pharmacology)
• RNA Interference
• Repressor Proteins
• STAT3 Transcription Factor (metabolism)
• Side-Population Cells (drug effects, metabolism, pathology)
• Signal Transduction (drug effects)
• Time Factors
• Transcription Factor RelA (metabolism)
• Transcription, Genetic
• Transfection
• Tumor Burden (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays