ArticlePloS one2013
Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 54 citations in OpenAlex.
- Small molecule screening identifies cytotoxic endoplasmic reticulum-associated degradation inhibitors in multiple myeloma.Cell death & disease · 2026Article
- GCN2 in Cancer: Molecular Mechanisms to Therapeutic Potential.Current cancer drug targets · 2026Review
- Harnessing p97/VCP: A Transformative AAA+ ATPase Target for Next-Generation Cancer Therapeutics.Cancers · 2025Review
- Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma.Clinical and experimental medicine · 2025Review
- Toward Understanding the Mechanism of Client-Selective Small Molecule Inhibitors of the Sec61 Translocon.Journal of molecular recognition : JMR · 2025Review
- Oncogenic Mutant p53 Sensitizes Non-Small Cell Lung Cancer Cells to Proteasome Inhibition via Oxidative Stress-Dependent Induction of Mitochondrial Apoptosis.Cancer research communications · 2024Article
- Dual RNase activity of IRE1 as a target for anticancer therapies.Journal of cell communication and signaling · 2023Review
- Evaluation of the NRF1-proteasome axis as a therapeutic target in breast cancer.Scientific reports · 2023Article
- Article
- Pharmacological targeting of endoplasmic reticulum stress in disease.Nature reviews. Drug discovery · 2022Review
- Inhibitors of the Sec61 Complex and Novel High Throughput Screening Strategies to Target the Protein Translocation Pathway.International journal of molecular sciences · 2021Review
- Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer.International journal of molecular sciences · 2021Review
- p97/VCP inhibition causes excessive MRE11-dependent DNA end resection promoting cell killing after ionizing radiation.Cell reports · 2021Article
- Overcoming drug resistance by targeting protein homeostasis in multiple myeloma.Cancer drug resistance (Alhambra, Calif.) · 2021Article
- Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration.Molecular biology of the cell · 2020Article
- Proteotoxic Stress and Cell Death in Cancer Cells.Cancers · 2020Review
- Golgi organization is regulated by proteasomal degradation.Nature communications · 2020Article
- Disabling the Protease DDI2 Attenuates the Transcriptional Activity of NRF1 and Potentiates Proteasome Inhibitor Cytotoxicity.International journal of molecular sciences · 2020Article
- Novel p97/VCP inhibitor induces endoplasmic reticulum stress and apoptosis in both bortezomib-sensitive and -resistant multiple myeloma cells.Cancer science · 2019Article
- Uncoupling of p97 ATPase activity has a dominant negative effect on protein extraction.Scientific reports · 2019Article
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Authors and funding
14 authors at 5 institutions in 3 countries.
Funding
Abstract
Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER)-associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non-redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma.
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