Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells
The proteasome inhibitor bortezomib (BTZ) has emerged as an effective drug for the treatment of multiple myeloma even though many patients relapse from BTZ therapy. The present study investigated the metabolic pathways underlying the acquisition of bortezomib resistance in multiple myeloma. We used...
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MDPI AG
2020-04-01
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Series: | Biomolecules |
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Online Access: | https://www.mdpi.com/2218-273X/10/5/696 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Daniele Tibullo Cesarina Giallongo Alessandra Romano Nunzio Vicario Alessandro Barbato Fabrizio Puglisi Rosalba Parenti Angela Maria Amorini Miriam Wissam Saab Barbara Tavazzi Renata Mangione Maria Violetta Brundo Giacomo Lazzarino Giuseppe Alberto Palumbo Giovanni Li Volti Francesco Di Raimondo Giuseppe Lazzarino |
spellingShingle |
Daniele Tibullo Cesarina Giallongo Alessandra Romano Nunzio Vicario Alessandro Barbato Fabrizio Puglisi Rosalba Parenti Angela Maria Amorini Miriam Wissam Saab Barbara Tavazzi Renata Mangione Maria Violetta Brundo Giacomo Lazzarino Giuseppe Alberto Palumbo Giovanni Li Volti Francesco Di Raimondo Giuseppe Lazzarino Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells Biomolecules bortezomib multiple myeloma oxidative stress metabolism hexosamine biosynthetic pathway |
author_facet |
Daniele Tibullo Cesarina Giallongo Alessandra Romano Nunzio Vicario Alessandro Barbato Fabrizio Puglisi Rosalba Parenti Angela Maria Amorini Miriam Wissam Saab Barbara Tavazzi Renata Mangione Maria Violetta Brundo Giacomo Lazzarino Giuseppe Alberto Palumbo Giovanni Li Volti Francesco Di Raimondo Giuseppe Lazzarino |
author_sort |
Daniele Tibullo |
title |
Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells |
title_short |
Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells |
title_full |
Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells |
title_fullStr |
Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells |
title_full_unstemmed |
Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells |
title_sort |
mitochondrial functions, energy metabolism and protein glycosylation are interconnected processes mediating resistance to bortezomib in multiple myeloma cells |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2020-04-01 |
description |
The proteasome inhibitor bortezomib (BTZ) has emerged as an effective drug for the treatment of multiple myeloma even though many patients relapse from BTZ therapy. The present study investigated the metabolic pathways underlying the acquisition of bortezomib resistance in multiple myeloma. We used two different clones of multiple myeloma cell lines exhibiting different sensitivities to BTZ (U266 and U266-R) and compared them in terms of metabolic profile, mitochondrial fitness and redox balance homeostasis capacity. Our results showed that the BTZ-resistant clone (U266-R) presented increased glycosylated UDP-derivatives when compared to BTZ-sensitive cells (U266), thus also suggesting higher activities of the hexosamine biosynthetic pathway (HBP), regulating not only protein <i>O-</i> and <i>N-</i>glycosylation but also mitochondrial functions. Notably, U266-R displayed increased mitochondrial biogenesis and mitochondrial dynamics associated with stronger antioxidant defenses. Furthermore, U266-R maintained a significantly higher concentration of substrates for protein glycosylation when compared to U266, particularly for UDP-GlcNac, thus further suggesting the importance of glycosylation in the BTZ pharmacological response. Moreover, BTZ-treated U266-R showed significantly higher ATP/ADP ratios and levels of ECP and also exhibited increased mitochondrial fitness and antioxidant response. In conclusions, our findings suggest that the HBP may play a major role in mitochondrial fitness, driving BTZ resistance in multiple myeloma and thus representing a possible target for new drug development for BTZ-resistant patients. |
topic |
bortezomib multiple myeloma oxidative stress metabolism hexosamine biosynthetic pathway |
url |
https://www.mdpi.com/2218-273X/10/5/696 |
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doaj-afb6104d5ad14a24a39567924c6114ba2020-11-25T03:11:24ZengMDPI AGBiomolecules2218-273X2020-04-011069669610.3390/biom10050696Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma CellsDaniele Tibullo0Cesarina Giallongo1Alessandra Romano2Nunzio Vicario3Alessandro Barbato4Fabrizio Puglisi5Rosalba Parenti6Angela Maria Amorini7Miriam Wissam Saab8Barbara Tavazzi9Renata Mangione10Maria Violetta Brundo11Giacomo Lazzarino12Giuseppe Alberto Palumbo13Giovanni Li Volti14Francesco Di Raimondo15Giuseppe Lazzarino16Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalySection of Haematology, Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, ItalyDivision of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, ItalySection of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyDivision of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, ItalyDivision of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, ItalySection of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalySection of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalySection of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyInstitute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, and Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyInstitute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, and Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, ItalyDepartment of Biological, Geological and Environmental Science, University of Catania, 95123 Catania, ItalyUniCamillus-Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, ItalySection of Haematology, Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, ItalySection of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyDivision of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, ItalySection of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, ItalyThe proteasome inhibitor bortezomib (BTZ) has emerged as an effective drug for the treatment of multiple myeloma even though many patients relapse from BTZ therapy. The present study investigated the metabolic pathways underlying the acquisition of bortezomib resistance in multiple myeloma. We used two different clones of multiple myeloma cell lines exhibiting different sensitivities to BTZ (U266 and U266-R) and compared them in terms of metabolic profile, mitochondrial fitness and redox balance homeostasis capacity. Our results showed that the BTZ-resistant clone (U266-R) presented increased glycosylated UDP-derivatives when compared to BTZ-sensitive cells (U266), thus also suggesting higher activities of the hexosamine biosynthetic pathway (HBP), regulating not only protein <i>O-</i> and <i>N-</i>glycosylation but also mitochondrial functions. Notably, U266-R displayed increased mitochondrial biogenesis and mitochondrial dynamics associated with stronger antioxidant defenses. Furthermore, U266-R maintained a significantly higher concentration of substrates for protein glycosylation when compared to U266, particularly for UDP-GlcNac, thus further suggesting the importance of glycosylation in the BTZ pharmacological response. Moreover, BTZ-treated U266-R showed significantly higher ATP/ADP ratios and levels of ECP and also exhibited increased mitochondrial fitness and antioxidant response. In conclusions, our findings suggest that the HBP may play a major role in mitochondrial fitness, driving BTZ resistance in multiple myeloma and thus representing a possible target for new drug development for BTZ-resistant patients.https://www.mdpi.com/2218-273X/10/5/696bortezomibmultiple myelomaoxidative stressmetabolismhexosamine biosynthetic pathway |