Targeting glucose consumption and autophagy in myeloma with the novel nucleoside analogue 8-aminoadenosine

Mala Shanmugam*, Samuel K. McBrayer, Jun Qian, Kiril Raikoff, Michael J. Avram, Seema Singhal, Varsha Gandhi, Paul T. Schumaker, Nancy L. Krett, Steven T. Rosen

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Multiple myeloma, an incurable plasma cell malignancy, is characterized by altered cellular metabolism and resistance to apoptosis. Recent connections between glucose metabolism and resistance to apoptosis provide a compelling rationale for targeting metabolic changes in cancer. In this study, we have examined the ability of the purine analogue 8-aminoadenosine to acutely reduce glucose consumption by regulating localization and expression of key glucose transporters. Myeloma cells counteracted the metabolic stress by activating autophagy. Co-treatment with inhibitors of autophagy results in marked enhancement of cell death. Glucose consumption by drug-resistant myeloma cells was unaffected by 8-aminoadenosine, and accordingly, no activation of autophagy was observed. However, these cells can be sensitized to 8-aminoadenosine under glucose-limiting conditions. The prosurvival autophagic response of myeloma to nutrient deprivation or to nucleoside analogue treatment has not been described previously. This study establishes the potential of metabolic targeting as a broader means to kill and sensitize myeloma and identifies a compound that can achieve this goal.

Original languageEnglish (US)
Pages (from-to)26816-26830
Number of pages15
JournalJournal of Biological Chemistry
Volume284
Issue number39
DOIs
StatePublished - Sep 25 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Shanmugam, M., McBrayer, S. K., Qian, J., Raikoff, K., Avram, M. J., Singhal, S., Gandhi, V., Schumaker, P. T., Krett, N. L., & Rosen, S. T. (2009). Targeting glucose consumption and autophagy in myeloma with the novel nucleoside analogue 8-aminoadenosine. Journal of Biological Chemistry, 284(39), 26816-26830. https://doi.org/10.1074/jbc.M109.000646