Cdc37 suppression induces plasma cell immaturation and bortezomib resistance in multiple myeloma via Xbp1s
| Autor: | Yan Xu, Bin Meng, Dehui Zou, Lugui Qiu, Qian Lei, Meirong Zang, Minghua Wu, Yangbowen Wu, Jiaojiao Guo, Yinghong Zhu, Xiangling Feng, Gang An, Shuhui Deng, Wen Zhou, Yongjun Guan, Lanting Liu, Mu Hao, Xiaoqi Qin, Fengyan Jin |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Drug resistance Plasma cell lcsh:RC254-282 Article 03 medical and health sciences 0302 clinical medicine In vivo Plasma cell differentiation medicine Molecular Biology Transcription factor Multiple myeloma Haematological cancer Bortezomib Chemistry Oncogenes medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 030104 developmental biology medicine.anatomical_structure Cell culture 030220 oncology & carcinogenesis Cancer research medicine.drug |
| Zdroj: | Oncogenesis Oncogenesis, Vol 9, Iss 3, Pp 1-13 (2020) |
| ISSN: | 2157-9024 |
| Popis: | Multiple myeloma (MM) is the second most prevalent hematologic malignancy. Although the use of bortezomib (BTZ) significantly improves MM therapy, intrinsic and acquired drug resistance to BTZ remains a major clinical problem. In this study, we find that Cdc37, a key co-chaperone of Hsp90, is downregulated in relapsed MM patients, especially after BTZ treatment, suggesting a link between Cdc37 and BTZ resistance. Suppression of Cdc37 or inhibition of Cdc37/Hsp90 association induces plasma cell dedifferentiation, quiescence of MM cells, and BTZ resistance in MM. Furthermore, we discover that Cdc37 expression correlates positively with Xbp1s, a critical transcription factor for plasma cell differentiation in MM samples. Depletion/inhibition of Cdc37 downregulates Xbp1s, while overexpression of Xbp1s in MM cell lines partially rescues plasma immaturation and BTZ resistance. It is suggested that Xbp1s may act as a key downstream effector of Cdc37. Experiments with a mouse model also demonstrate that Cdc37 inhibition promotes plasma cell immaturation, confers BTZ resistance, and increases MM progression in vivo. Together, we identify a critical factor and a new signaling mechanism that regulate plasma cell immaturation and BTZ resistance in MM cells. Our findings may constitute a novel strategy that overcomes BTZ resistance in MM therapy. |
| Databáze: | OpenAIRE |
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