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Inhibition of TLR4 Signaling Affects Mitochondrial Fitness and Overcomes Bortezomib Resistance in Myeloma Plasma Cells

1
Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
2
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
3
Division of Hematology, Azienda Ospedaliero Universitaria, Policlinico Vittorio Emanuele, 95123 Catania, Italy
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Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
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Fondazione “Istituto Oncologico del Mediterraneo”, 95029 Catania, Italy
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Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123 Catania, Italy
*
Authors to whom correspondence should be addressed.
These authors contributed equally as Co-First.
These authors contributed equally as Co-Last.
Cancers 2020, 12(8), 1999; https://doi.org/10.3390/cancers12081999
Received: 25 May 2020 / Revised: 2 July 2020 / Accepted: 18 July 2020 / Published: 22 July 2020
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. View Full-Text
Keywords: TLR4; myeloma; bortezomib resistance; mitochondria; refractory CD138+ TLR4; myeloma; bortezomib resistance; mitochondria; refractory CD138+
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MDPI and ACS Style

Giallongo, C.; Tibullo, D.; Puglisi, F.; Barbato, A.; Vicario, N.; Cambria, D.; Parrinello, N.L.; Romano, A.; Conticello, C.; Forte, S.; Parenti, R.; Amorini, A.M.; Lazzarino, G.; Li Volti, G.; Palumbo, G.A.; Di Raimondo, F. Inhibition of TLR4 Signaling Affects Mitochondrial Fitness and Overcomes Bortezomib Resistance in Myeloma Plasma Cells. Cancers 2020, 12, 1999. https://doi.org/10.3390/cancers12081999

AMA Style

Giallongo C, Tibullo D, Puglisi F, Barbato A, Vicario N, Cambria D, Parrinello NL, Romano A, Conticello C, Forte S, Parenti R, Amorini AM, Lazzarino G, Li Volti G, Palumbo GA, Di Raimondo F. Inhibition of TLR4 Signaling Affects Mitochondrial Fitness and Overcomes Bortezomib Resistance in Myeloma Plasma Cells. Cancers. 2020; 12(8):1999. https://doi.org/10.3390/cancers12081999

Chicago/Turabian Style

Giallongo, Cesarina, Daniele Tibullo, Fabrizio Puglisi, Alessandro Barbato, Nunzio Vicario, Daniela Cambria, Nunziatina L. Parrinello, Alessandra Romano, Concetta Conticello, Stefano Forte, Rosalba Parenti, Angela M. Amorini, Giuseppe Lazzarino, Giovanni Li Volti, Giuseppe A. Palumbo, and Francesco Di Raimondo. 2020. "Inhibition of TLR4 Signaling Affects Mitochondrial Fitness and Overcomes Bortezomib Resistance in Myeloma Plasma Cells" Cancers 12, no. 8: 1999. https://doi.org/10.3390/cancers12081999

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