Mitochondrial modulation decreases the bortezomib-resistance in multiple myeloma cells

Authors

  • I.S. Song,

    1. National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea
    Search for more papers by this author
    • I.-S.S. and H.-K.K. contributed equally to this manuscript

  • H.K. Kim,

    1. National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea
    Search for more papers by this author
    • I.-S.S. and H.-K.K. contributed equally to this manuscript

  • S.R. Lee,

    1. National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea
    Search for more papers by this author
  • S.H. Jeong,

    1. National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea
    Search for more papers by this author
  • N. Kim,

    1. National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea
    Search for more papers by this author
  • K.S. Ko,

    1. National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea
    Search for more papers by this author
  • B.D. Rhee,

    1. National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea
    Search for more papers by this author
  • J. Han

    Corresponding author
    • National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, Busan, Korea
    Search for more papers by this author

  • Conflicts of interest: The authors have no potential conflicts of interest, including specific financial interests, relationships, or affiliations relevant to the subject of this manuscript.

Correspondence to: Jin Han, MD, PhD, National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Inje University, 633-165 Gaegeum-dong, Busanjin-gu, Busan 614-735, Korea, Tel.: [82-51-890-6727], Fax: +[82-51-894-5714], E-mail: phyhanj@inje.ac.kr

Abstract

Multiple myeloma (MM) is an incurable hematological malignancy that causes most patients to eventually relapse and die from their disease. The 20S proteasome inhibitor bortezomib has emerged as an effective drug for MM treatment; however, intrinsic and acquired resistance to bortezomib has already been observed in MM patients. We evaluated the involvement of mitochondria in resistance to bortezomib-induced cell death in two different MM cell lines (bortezomib-resistant KMS20 cells and bortezomib-sensitive KMS28BM cells). Indices of mitochondrial function, including membrane potential, oxygen consumption rate and adenosine-5′-triphosphate and mitochondrial Ca2+ concentrations, were positively correlated with drug resistance of KMS cell lines. Mitochondrial genes including CYPD, SOD2 and MCU were differentially expressed in KMS cells. Thus, changes in the expression of these genes lead to changes in mitochondrial activity and in bortezomib susceptibility or resistance, and their combined effect contributes to differential sensitivity or resistance of MM cells to bortezomib. In support of this finding, coadministration of bortezomib and 2-methoxyestradiol, a SOD inhibitor, rendered KMS20 cells sensitive to apoptosis. Our results provide new insight into therapeutic modalities for MM patients. Studying mitochondrial activity and specific mitochondrial gene expression in fresh MM specimens might help predict resistance to proapoptotic chemotherapies and inform clinical decision-making.

Ancillary