دورية أكاديمية
RARγ activation sensitizes human myeloma cells to carfilzomib treatment through the OAS-RNase L innate immune pathway.
| العنوان: | RARγ activation sensitizes human myeloma cells to carfilzomib treatment through the OAS-RNase L innate immune pathway. |
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| المؤلفون: | Wang Q; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Lin Z; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas.; Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China., Wang Z; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Ye L; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Xian M; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Xiao L; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Su P; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Bi E; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Huang YH; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Qian J; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Liu L; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Ma X; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Yang M; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Xiong W; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas., Zu Y; Department of Pathology and Genomic Medicine, Institute for Academic Medicine, Houston Methodist Research Institute, Houston, Texas; and., Pingali SR; Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas., Xu B; Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China., Yi Q; Center for Translational Research in Hematological Malignancies, Houston Methodist Cancer Center/Houston Methodist Research Institute, Houston, Texas. |
| المصدر: | Blood [Blood] 2022 Jan 06; Vol. 139 (1), pp. 59-72. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Antineoplastic Agents/*pharmacology , Immunity, Innate/*drug effects , Multiple Myeloma/*drug therapy , Oligopeptides/*pharmacology , Receptors, Retinoic Acid/*agonists, 2',5'-Oligoadenylate Synthetase/immunology ; Cell Line, Tumor ; Endoribonucleases/immunology ; Humans ; Receptors, Retinoic Acid/immunology ; Tumor Cells, Cultured ; Retinoic Acid Receptor gamma |
| مستخلص: | Proteasome inhibitors (PIs) such as bortezomib (Btz) and carfilzomib (Cfz) are highly efficacious for patients with multiple myeloma (MM). However, relapses are frequent, and acquired resistance to PI treatment emerges in most patients. Here, we performed a high-throughput screen of 1855 Food and Drug Administration (FDA)-approved drugs and identified all-trans retinoic acid (ATRA), which alone has no antimyeloma effect, as a potent drug that enhanced MM sensitivity to Cfz-induced cytotoxicity and resensitized Cfz-resistant MM cells to Cfz in vitro. ATRA activated retinoic acid receptor (RAR)γ and interferon-β response pathway, leading to upregulated expression of IRF1. IRF1 in turn initiated the transcription of OAS1, which synthesized 2-5A upon binding to double-stranded RNA (dsRNA) induced by Cfz and resulted in cellular RNA degradation by RNase L and cell death. Similar to ATRA, BMS961, a selective RARγ agonist, could also (re)sensitize MM cells to Cfz in vitro, and both ATRA and BMS961 significantly enhanced the therapeutic effects of Cfz in established MM in vivo. In support of these findings, analyses of large datasets of patients' gene profiling showed a strong and positive correlation between RARγ and OAS1 expression and patient's response to PI treatment. Thus, this study highlights the potential for RARγ agonists to sensitize and overcome MM resistance to Cfz treatment in patients. (© 2022 by The American Society of Hematology.) |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Oligopeptides) 0 (Receptors, Retinoic Acid) 72X6E3J5AR (carfilzomib) EC 2.7.7.- (OAS1 protein, human) EC 2.7.7.84 (2',5'-Oligoadenylate Synthetase) EC 3.1.- (Endoribonucleases) EC 3.1.26.- (2-5A-dependent ribonuclease) |
| تواريخ الأحداث: | Date Created: 20210819 Date Completed: 20220223 Latest Revision: 20231213 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1182/blood.2020009856 |
| PMID: | 34411225 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood.2020009856 |