Targeting glucose consumption and autophagy in myeloma with the novel nucleoside analogue 8-aminoadenosine.
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.
Shanmugam
Mala
M
Robert H Lurie Comprehensive Cancer Center, MD Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA. mala@northwestern.edu
McBrayer
Samuel K
SK
Qian
Jun
J
Raikoff
Kiril
K
Avram
Michael J
MJ
Singhal
Seema
S
Gandhi
Varsha
V
Schumacker
Paul T
PT
Krett
Nancy L
NL
Rosen
Steven T
ST
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002738:Chloroquine / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; C010533:8-aminoadenosine; D002738:Chloroquine; D000255:Adenosine Triphosphate; D005947:Glucose; D000241:Adenosine