ArticleCancers2020
Inhibition of TLR4 Signaling Affects Mitochondrial Fitness and Overcomes Bortezomib Resistance in Myeloma Plasma Cells.
Article in Cancers, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 51 citations in OpenAlex.
- Review
- Article
- Emerging roles of RNA mInternational journal of oncology · 2026Review
- Mechanisms and intervention strategies of microenvironment-mediated drug resistance in multiple myeloma.Cancer cell international · 2026Review
- Carnosine protects human microglia against Aβ oligomers through a multimodal mechanism of action: inhibition of oxidative stress, rescue of cellular energy status, and enhancement of phagocytosis.Frontiers in immunology · 2026Article
- Review
- (+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease.Journal of translational medicine · 2024Article
- Toll-like receptor signaling in multiple myeloma cells promotes the expression of pro-survival genes B-cell lymphoma 2 and MYC and modulates the expression of B-cell maturation antigen.Frontiers in immunology · 2024Article
- Mitochondrial electron transport chain in macrophage reprogramming: Potential role in antibacterial immune response.Current research in immunology · 2024Review
- Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers.Biomolecules · 2023Review
- Anaplastic thyroid cancer cells reduce CD71 levels to increase iron overload tolerance.Journal of translational medicine · 2023Article
- Lactate trafficking inhibition restores sensitivity to proteasome inhibitors and orchestrates immuno-microenvironment in multiple myeloma.Cell proliferation · 2023Article
- Ectopic CH60 mediates HAPLN1-induced cell survival signaling in multiple myeloma.Life science alliance · 2023Article
- Characterization of Carnosine Effect on Human Microglial Cells under Basal Conditions.Biomedicines · 2023Article
- Role of NF-κB Signaling in the Interplay between Multiple Myeloma and Mesenchymal Stromal Cells.International journal of molecular sciences · 2023Review
- Microfluidic/HPLC combination to study carnosine protective activity on challenged human microglia: Focus on oxidative stress and energy metabolism.Frontiers in pharmacology · 2023Article
- Targeting CAM-DR and Mitochondrial Transfer for the Treatment of Multiple Myeloma.Current oncology (Toronto, Ont.) · 2022Review
- Neuroprotective Role of α-Lipoic Acid in Iron-Overload-Mediated Toxicity and Inflammation in In Vitro and In Vivo Models.Antioxidants (Basel, Switzerland) · 2022Article
- TLR4 Signaling and Heme Oxygenase-1/Carbon Monoxide Pathway Crosstalk Induces Resiliency of Myeloma Plasma Cells to Bortezomib Treatment.Antioxidants (Basel, Switzerland) · 2022Article
- Modulation of Cellular Redox Parameters for Improving Therapeutic Responses in Multiple Myeloma.Antioxidants (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
Multiple myeloma (MM) is a B-cell malignancy requiring inflammatory microenvironment signals for cell survival and proliferation. Despite improvements in pharmacological tools, MM remains incurable mainly because of drug resistance. The present study aimed to investigate the implication of Toll-like receptor 4 (TLR4) as the potential mechanism of bortezomib (BTZ) resistance. We found that TLR4 activation induced mitochondrial biogenesis and increased mitochondrial mass in human MM cell lines. Moreover, TLR4 signaling was activated after BTZ exposure and was increased in BTZ-resistant U266 (U266-R) cells. A combination of BTZ with TAK-242, a selective TLR4 inhibitor, overcame drug resistance through the generation of higher and extended oxidative stress, strong mitochondrial depolarization and severe impairment of mitochondrial fitness which in turn caused cell energy crisis and activated mitophagy and apoptosis. We further confirmed the efficacy of a TAK-242/BTZ combination in plasma cells from refractory myeloma patients. Consistently, inhibition of TLR4 increased BTZ-induced mitochondrial depolarization, restoring pharmacological response. Taken together, these findings indicate that TLR4 signaling acts as a stress-responsive mechanism protecting mitochondria during BTZ exposure, sustaining mitochondrial metabolism and promoting drug resistance. Inhibition of TLR4 could be therefore be a possible target in patients with refractory MM to overcome BTZ resistance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.