Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells
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
Affiliations
Daniele Tibullo
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Cesarina Giallongo
Section of Haematology, Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
Alessandra Romano
Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, Italy
Nunzio Vicario
Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Alessandro Barbato
Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, Italy
Fabrizio Puglisi
Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, Italy
Rosalba Parenti
Section of Physiology, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Angela Maria Amorini
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Miriam Wissam Saab
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Barbara Tavazzi
Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, and Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
Renata Mangione
Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, and Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
Maria Violetta Brundo
Department of Biological, Geological and Environmental Science, University of Catania, 95123 Catania, Italy
Giacomo Lazzarino
UniCamillus-Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy
Giuseppe Alberto Palumbo
Section of Haematology, Department of Medical and Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95123 Catania, Italy
Giovanni Li Volti
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
Francesco Di Raimondo
Division of Hematology, Department of General Surgery and Medical-Surgical Specialties, A.O.U. “Policlinico-Vittorio Emanuele”, University of Catania, 95123 Catania, Italy
Giuseppe Lazzarino
Section of Biochemistry, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
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 O- and N-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.
