Proteasome subunit PSMD1 is a key therapeutic target in multiple myeloma
Abstract
Abstract We found that PSMD1, a key subunit of the 19S proteasome regulatory particle, was overexpressed and correlated with poor prognosis in multiple myeloma (MM). Genetic depletion of PSMD1 decreased cancer cell viability, induced polyubiquitinated protein accumulation, and promoted apoptosis. Proteomic analysis revealed the activation of immune-related pathways, suggesting the potential for immune modulation. Targeting PSMD1 with small interfering RNA (siRNA), delivered via lipid nanoparticles (LNPs), reduced tumor growth in MM cell lines and primary patient samples while sparing normal cells. It also overcame proteasome inhibitor resistance and the protective effects of the bone marrow milieu. In MM xenograft mouse models, PSMD1 siRNA LNPs significantly reduced tumor growth and prolonged survival. In addition, PSMD1 depletion had similar effects on other types of cancer cell lines. These findings position PSMD1 as a critical target in cancer therapy, with broad implications for overcoming drug resistance, improving therapeutic outcomes, and potentially affecting immune responses across various cancers. These findings provide a foundation for the clinical development of PSMD1-targeted therapies in myeloma and other malignancies.
Article Details
Authors (19)
Ting Du
Teng Fang
School of Airspace Science and Engineering, Shandong University 1 , Weihai 264209,
Sindhu Pillai
1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
Arghya Ray
1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
Minxing Wang
1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
Xueping Wan
1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
Kenneth Wen
1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
Yuntong Liu
1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
Jingyu Xu
1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
Md Abu Musa
1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
Xiangdong Liu
Mariateresa Fulciniti
Dana Farber Cancer Institute, Boston, Massachusetts, United States
Nikhil C. Munshi
Filip Garbicz
Ruben D. Carrasco
Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, United States
Yao Yao
Zhongkun Zhang
1Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
Yan Song
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University
Kenneth C. Anderson