| Autor: |
Crawford LJ; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK. lisa.crawford@qub.ac.uk., Campbell DC; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Morgan JJ; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Lawson MA; Department of Oncology and Metabolism, Sheffield Myeloma Research Team, Medical School, University of Sheffield, Sheffield, UK., Down JM; Department of Oncology and Metabolism, Sheffield Myeloma Research Team, Medical School, University of Sheffield, Sheffield, UK., Chauhan D; Department of Medical Oncology, The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., McAvera RM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Morris TC; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Hamilton C; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK., Krishnan A; Cell Biology Unit, University Medical Center Mainz, Mainz, Germany., Rajalingam K; Cell Biology Unit, University Medical Center Mainz, Mainz, Germany., Chantry AD; Department of Oncology and Metabolism, Sheffield Myeloma Research Team, Medical School, University of Sheffield, Sheffield, UK., Irvine AE; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK. |
| Abstrakt: |
Proteasome inhibitors have provided a significant advance in the treatment of multiple myeloma (MM). Consequently, there is increasing interest in developing strategies to target E3 ligases, de-ubiquitinases, and/or ubiquitin receptors within the ubiquitin proteasome pathway, with an aim to achieve more specificity and reduced side-effects. Previous studies have shown a role for the E3 ligase HUWE1 in modulating c-MYC, an oncogene frequently dysregulated in MM. Here we investigated HUWE1 in MM. We identified elevated expression of HUWE1 in MM compared with normal cells. Small molecule-mediated inhibition of HUWE1 resulted in growth arrest of MM cell lines without significantly effecting the growth of normal bone marrow cells, suggesting a favorable therapeutic index. Studies using a HUWE1 knockdown model showed similar growth inhibition. HUWE1 expression positively correlated with MYC expression in MM bone marrow cells and correspondingly, genetic knockdown and biochemical inhibition of HUWE1 reduced MYC expression in MM cell lines. Proteomic identification of HUWE1 substrates revealed a strong association of HUWE1 with metabolic processes in MM cells. Intracellular glutamine levels are decreased in the absence of HUWE1 and may contribute to MYC degradation. Finally, HUWE1 depletion in combination with lenalidomide resulted in synergistic anti-MM activity in both in vitro and in vivo models. Taken together, our data demonstrate an important role of HUWE1 in MM cell growth and provides preclinical rationale for therapeutic strategies targeting HUWE1 in MM. |
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