IL-18-induced interaction between IMP3 and HuR contributes to COX-2 mRNA stabilization in acute myeloid leukemia.
Acute myeloid leukemia is the majority type presented in leukemia patients. Forcing malignant cells to undergo differentiation is 1 strategy for acute myeloid leukemia therapy. However, the failure of acute myeloid leukemia patients to achieve remission as a result of drug resistance remains a challenge. In this study, we found that the abundances of the proinflammatory cytokine IL-18 and its receptor (IL-18R) correlated with the occurrence of drug resistance in AML patients during standard treatment. Cyclooxygenase 2 (COX-2) has been suggested to have an antiapoptotic role in chemoresistant cancer cells. IL-18 treatment resulted in an increase in COX-2 expression through the post-transcriptional regulation of COX-2 mRNA in differentiated U937 cells and showed antiapoptotic activity in U937 and THP-1 cells. Two RNA-binding proteins, human antigen R and insulin-like growth factor mRNA-binding protein 3, mediated the stabilization of COX-2 mRNA. IL-18 induced the shuttling of human antigen R and insulin-like growth factor mRNA-binding protein 3 from the nucleus to the cytoplasm and facilitated their interaction; subsequently, this complex bound to the 3' untranslated region of COX-2 mRNA and affected its stability. We demonstrated further that JNK and/or ERK1/2 regulated human antigen R nucleocytoplasmic shuttling, mediating IL-18 stabilization of cyclooxygenase 2 mRNA.
*Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, and Center for Neurotrauma and Neuroregeneration and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan; Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan; Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan; and **Institute of Bioinformatics and Biosignal Transduction and Infectious Disease and Signaling Research Center and Center of Molecular Inflammation, National Cheng Kung University, Tainan, Taiwan.
Chiung-Yuan
CY
Ko
*Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, and Center for Neurotrauma and Neuroregeneration and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan; Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan; Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan; and **Institute of Bioinformatics and Biosignal Transduction and Infectious Disease and Signaling Research Center and Center of Molecular Inflammation, National Cheng Kung University, Tainan, Taiwan.
Wen-Ling
WL
Wang
*Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, and Center for Neurotrauma and Neuroregeneration and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan; Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan; Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan; and **Institute of Bioinformatics and Biosignal Transduction and Infectious Disease and Signaling Research Center and Center of Molecular Inflammation, National Cheng Kung University, Tainan, Taiwan.
Chien-Feng
CF
Li
*Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, and Center for Neurotrauma and Neuroregeneration and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan; Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan; Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan; and **Institute of Bioinformatics and Biosignal Transduction and Infectious Disease and Signaling Research Center and Center of Molecular Inflammation, National Cheng Kung University, Tainan, Taiwan.
Yung-Ming
YM
Jeng
*Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, and Center for Neurotrauma and Neuroregeneration and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan; Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan; Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan; and **Institute of Bioinformatics and Biosignal Transduction and Infectious Disease and Signaling Research Center and Center of Molecular Inflammation, National Cheng Kung University, Tainan, Taiwan.
Yu-Yi
YY
Chu
*Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, and Center for Neurotrauma and Neuroregeneration and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan; Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan; Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan; and **Institute of Bioinformatics and Biosignal Transduction and Infectious Disease and Signaling Research Center and Center of Molecular Inflammation, National Cheng Kung University, Tainan, Taiwan.
Han-Ying
HY
Wang
*Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, and Center for Neurotrauma and Neuroregeneration and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan; Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan; Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan; and **Institute of Bioinformatics and Biosignal Transduction and Infectious Disease and Signaling Research Center and Center of Molecular Inflammation, National Cheng Kung University, Tainan, Taiwan.
Joseph T
JT
Tseng
*Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, and Center for Neurotrauma and Neuroregeneration and Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan; Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan; Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Department of Biotechnology, Southern Taiwan University, Tainan, Taiwan; Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan; and **Institute of Bioinformatics and Biosignal Transduction and Infectious Disease and Signaling Research Center and Center of Molecular Inflammation, National Cheng Kung University, Tainan, Taiwan yumingw@mail.ncku.edu.tw.
Ju-Ming
JM
Wang
D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics*; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism* / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015533:Transcriptional Activation
D000067780:ELAV-Like Protein 1; C498780:IGF2BP3 protein, human; D020382:Interleukin-18; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051546:Cyclooxygenase 2
differentiation therapy; drug resistance; post-transcriptional regulation