Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma
| العنوان: | Downregulation of PA28α induces proteasome remodeling and results in resistance to proteasome inhibitors in multiple myeloma |
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| المؤلفون: | Jonathan L. Kaufman, Craig C. Hofmeister, Yanyan Gu, Ajay K. Nooka, Benjamin G. Barwick, Lawrence H. Boise, Mala Shanmugam, Vikas Gupta, Sagar Lonial, Madhav V. Dhodapkar |
| المصدر: | Blood Cancer Journal, Vol 10, Iss 12, Pp 1-10 (2020) Blood Cancer Journal |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Proteasome Endopeptidase Complex, Down-Regulation, Muscle Proteins, Myeloma, Plasma cell, lcsh:RC254-282, Article, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Cell Line, Tumor, medicine, Humans, Multiple myeloma, Eukaryotic cell, biology, Chemistry, Activator (genetics), Hematology, Translational research, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Cell biology, Gene Expression Regulation, Neoplastic, Protein catabolism, 030104 developmental biology, medicine.anatomical_structure, Oncology, Proteasome, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, biology.protein, Antibody, Multiple Myeloma, Proteasome Inhibitors |
| الوصف: | Protein homeostasis is critical for maintaining eukaryotic cell function as well as responses to intrinsic and extrinsic stress. The proteasome is a major portion of the proteolytic machinery in mammalian cells and plays an important role in protein homeostasis. Multiple myeloma (MM) is a plasma cell malignancy with high production of immunoglobulins and is especially sensitive to treatments that impact protein catabolism. Therapeutic agents such as proteasome inhibitors have demonstrated significant benefit for myeloma patients in all treatment phases. Here, we demonstrate that the 11S proteasome activator PA28α is upregulated in MM cells and is key for myeloma cell growth and proliferation. PA28α also regulates MM cell sensitivity to proteasome inhibitors. Downregulation of PA28α inhibits both proteasomal load and activity, resulting in a change in protein homeostasis less dependent on the proteasome and leads to cell resistance to proteasome inhibitors. Thus, our findings suggest an important role of PA28α in MM biology, and also provides a new approach for targeting the ubiquitin-proteasome system and ultimately sensitivity to proteasome inhibitors. |
| تدمد: | 2044-5385 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e633d2202ef6627d38e371fc9557fd51Test https://doi.org/10.1038/s41408-020-00393-0Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e633d2202ef6627d38e371fc9557fd51 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20445385 |
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