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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number696
JournalBiomolecules
Volume10
Issue number5
DOIs
Publication statusPublished - May 2020

Keywords

  • Bortezomib
  • Hexosamine biosynthetic pathway
  • Metabolism
  • Multiple myeloma
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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