title: Bortezomib inhibits Burkitt's lymphoma cell proliferation by downregulating sumoylated hnRNP K and c-Myc expression.
abstract: Bortezomib (Velcal) was the first proteasome inhibitor to be approved by the US Food and Drug Administration to treat patients with relapsed/refractory multiple myelomas. Previous studies have demonstrated that bortezomib inhibits tumor cell proliferation and induces apoptosis by blocking the nuclear factor (NF)-κB pathway. However, the exact mechanism by which bortezomib induces cancer cell apoptosis is still not well understood. In this study, we found that bortezomib significantly inhibited cell proliferation in both human Burkitt's lymphoma CA46 and Daudi cells. Through proteomic analysis, we found that bortezomib treatment changed the expression of various proteins in distinct functional categories including unfolding protein response (UPS), RNA processing, protein targeting and biosynthesis, apoptosis, and signal transduction. Among the proteins with altered expression, hnRNP K, hnRNP H, Hsp90α, Grp78, and Hsp7C were common to both Daudi and CA46 cells. Interestingly, bortezomib treatment downregulated the expression of high-molecular-weight (HMw) hnRNP K and c-Myc but upregulated the expression of low-molecular-weight (LMw) hnRNP K. Moreover, cell proliferation was significantly correlated with high expression of HMw hnRNP K and c-Myc. HMw and LMw hnRNP K were identified as sumoylated and desumoylated hnRNP K, respectively. Using transient transfection, we found that sumoylated hnRNP K increased c-Myc expression at the translational level and contributed to cell proliferation, and that Lys422 of hnRNP K is the candidate sumoylated residue. Our results suggest that besides inhibiting the ubiquitin-proteasome pathway, bortezomib may inhibit cell proliferation by downregulating sumoylated hnRNP K and c-Myc expression in Burkitt's lymphoma cells.
authors: Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.|Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Fat-Moon
authors: FM
authors: Suk
authors: Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan.|Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Shyr-Yi
authors: SY
authors: Lin
authors: Department of Primary Care Medicine, Taipei Medical University Hospital, Taipei, Taiwan.|Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Ren-Jye
authors: RJ
authors: Lin
authors: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors: Yung-Hsin
authors: YH
authors: Hsine
authors: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors: Yen-Ju
authors: YJ
authors: Liao
authors: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors: Sheng-Uei
authors: SU
authors: Fang
authors: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.|Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
authors: Yu-Chih
authors: YC
authors: Liang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000069286:Bortezomib / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D000091342:Endoplasmic Reticulum Chaperone BiP; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D040901:Proteomics / Q000379:methods; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D058207:Sumoylation
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D016271:Proto-Oncogene Proteins c-myc; D000069286:Bortezomib; D008239:Lysine
keywords: Bortezomib; Burkitt’s lymphoma; c-Myc; hnRNP K; sumoylation