Ribosomal Biogenesis and Translational Flux Inhibition by the Selective Inhibitor of Nuclear Export (SINE) XPO1 Antagonist KPT-185.
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by the aberrant expression of several growth-regulating, oncogenic effectors. Exportin 1 (XPO1) mediates the nucleocytoplasmic transport of numerous molecules including oncogenic growth-regulating factors, RNAs, and ribosomal subunits. In MCL cells, the small molecule KPT-185 blocks XPO1 function and exerts anti-proliferative effects. In this study, we investigated the molecular mechanisms of this putative anti-tumor effect on MCL cells using cell growth/viability assays, immunoblotting, gene expression analysis, and absolute quantification proteomics. KPT-185 exhibited a p53-independent anti-lymphoma effect on MCL cells, by suppression of oncogenic mediators (e.g., XPO1, cyclin D1, c-Myc, PIM1, and Bcl-2 family members), repression of ribosomal biogenesis, and downregulation of translation/chaperone proteins (e.g., PIM2, EEF1A1, EEF2, and HSP70) that are part of the translational/transcriptional network regulated by heat shock factor 1. These results elucidate a novel mechanism in which ribosomal biogenesis appears to be a key component through which XPO1 contributes to tumor cell survival. Thus, we propose that the blockade of XPO1 could be a promising, novel strategy for the treatment of MCL and other malignancies overexpressing XPO1.
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States of America; Department of Clinical Laboratory Medicine, Biomedical Research Center Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Yoko
Y
Tabe
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States of America.
Kensuke
K
Kojima
Department of Clinical Laboratory Medicine, Biomedical Research Center Graduate School of Medicine, Juntendo University, Tokyo, Japan; Leading Center for the Development and Research of Cancer Medicine, Biomedical Research Center Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Shinichi
S
Yamamoto
Department of Clinical Laboratory Medicine, Biomedical Research Center Graduate School of Medicine, Juntendo University, Tokyo, Japan; Leading Center for the Development and Research of Cancer Medicine, Biomedical Research Center Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Kazumasa
K
Sekihara
Department of Laboratory Medicine, Tokai University of Medicine, Kanagawa, Japan.
Hiromichi
H
Matsushita
Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States of America.
Richard Eric
RE
Davis
Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States of America.
Zhiqiang
Z
Wang
Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States of America.
Wencai
W
Ma
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States of America.
Jo
J
Ishizawa
Laboratory of Proteomics and Biomolecular Science, Biomedical Research Center Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Saiko
S
Kazuno
Karyopharm Therapeutics Inc., Natick, MA, United States of America.
Michael
M
Kauffman
Karyopharm Therapeutics Inc., Natick, MA, United States of America.
Sharon
S
Shacham
Laboratory of Proteomics and Biomolecular Science, Biomedical Research Center Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Tsutomu
T
Fujimura
Laboratory of Proteomics and Biomolecular Science, Biomedical Research Center Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Takashi
T
Ueno
Department of Clinical Laboratory Medicine, Biomedical Research Center Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Takashi
T
Miida
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States of America.
Michael
M
Andreeff
D000179:Acrylates / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D054736:Elongation Factor 2 Kinase / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001678:Organelle Biogenesis; D020648:Peptide Elongation Factor 1 / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097606:Exportin 1 Protein
D000179:Acrylates; D000970:Antineoplastic Agents; D019938:Cyclin D1; D004268:DNA-Binding Proteins; D054736:Elongation Factor 2 Kinase; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D028884:Karyopherins; D020648:Peptide Elongation Factor 1; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D051573:Proto-Oncogene Proteins c-pim-1; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C094814:EEF1A1 protein, human; C576639:KPT-185; C490587:PIM2 protein, human; C517689:EEF2K protein, human; C496634:PIM1 protein, human