title: Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy.
abstract: Multiple myeloma is one of numerous malignancies characterized by increased glucose consumption, a phenomenon with significant prognostic implications in this disease. Few studies have focused on elucidating the molecular underpinnings of glucose transporter (GLUT) activation in cancer, knowledge that could facilitate identification of promising therapeutic targets. To address this issue, we performed gene expression profiling studies involving myeloma cell lines and primary cells as well as normal lymphocytes to uncover deregulated GLUT family members in myeloma. Our data demonstrate that myeloma cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption, maintenance of Mcl-1 expression, growth, and survival. We also establish that the activities of the enigmatic transporters GLUT8 and GLUT11 are required for proliferation and viability in myeloma, albeit because of functionalities probably distinct from whole-cell glucose supply. As proof of principle regarding the therapeutic potential of GLUT-targeted compounds, we include evidence of the antimyeloma effects elicited against both cell lines and primary cells by the FDA-approved HIV protease inhibitor ritonavir, which exerts a selective off-target inhibitory effect on GLUT4. Our work reveals critical roles for novel GLUT family members and highlights a therapeutic strategy entailing selective GLUT inhibition to specifically target aberrant glucose metabolism in cancer.
authors.affiliation: Division of Hematology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E Superior St, Chicago, IL 60611, USA.
authors.forename: Samuel K
authors.initials: SK
authors.lastname: McBrayer
authors.forename: Javelin C
authors.initials: JC
authors.lastname: Cheng
authors.forename: Seema
authors.initials: S
authors.lastname: Singhal
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Krett
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.forename: Mala
authors.initials: M
authors.lastname: Shanmugam
mesh_terms: D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051275:Glucose Transporter Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods / Q000639:trends; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D056687:Off-Label Use; D061251:Primary Cell Culture; D019438:Ritonavir / Q000494:pharmacology
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D051275:Glucose Transporter Type 4; D017320:HIV Protease Inhibitors; C439386:SLC2A11 protein, human; C495692:SLC2A4 protein, human; C405325:SLC2A8 protein, human; D005947:Glucose; D019438:Ritonavir