Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: Implications for glucose transporter-directed therapy

Samuel K. McBrayer, Javelin C. Cheng, Seema Singhal, Nancy L. Krett, Steven T. Rosen, Mala Shanmugam

Research output: Contribution to journalArticle

76 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4686-4697
Number of pages12
JournalBlood
Volume119
Issue number20
DOIs
StatePublished - May 17 2012
Externally publishedYes

Fingerprint

Facilitative Glucose Transport Proteins
Multiple Myeloma
Glucose
Cells
HIV Protease Inhibitors
Enzyme inhibition
Therapeutics
Cell Line
Ritonavir
Neoplasms
Lymphocytes
Gene Expression Profiling
Metabolism
Gene expression
Chemical activation
Maintenance
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11 : Implications for glucose transporter-directed therapy. / McBrayer, Samuel K.; Cheng, Javelin C.; Singhal, Seema; Krett, Nancy L.; Rosen, Steven T.; Shanmugam, Mala.

In: Blood, Vol. 119, No. 20, 17.05.2012, p. 4686-4697.

Research output: Contribution to journalArticle

McBrayer, Samuel K. ; Cheng, Javelin C. ; Singhal, Seema ; Krett, Nancy L. ; Rosen, Steven T. ; Shanmugam, Mala. / Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11 : Implications for glucose transporter-directed therapy. In: Blood. 2012 ; Vol. 119, No. 20. pp. 4686-4697.
@article{af2c0e27097f4634808a642c4713d698,
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.",
author = "McBrayer, {Samuel K.} and Cheng, {Javelin C.} and Seema Singhal and Krett, {Nancy L.} and Rosen, {Steven T.} and Mala Shanmugam",
year = "2012",
month = "5",
day = "17",
doi = "10.1182/blood-2011-09-377846",
language = "English (US)",
volume = "119",
pages = "4686--4697",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "20",

}

TY - JOUR

T1 - Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11

T2 - Implications for glucose transporter-directed therapy

AU - McBrayer, Samuel K.

AU - Cheng, Javelin C.

AU - Singhal, Seema

AU - Krett, Nancy L.

AU - Rosen, Steven T.

AU - Shanmugam, Mala

PY - 2012/5/17

Y1 - 2012/5/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84861215287&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861215287&partnerID=8YFLogxK

U2 - 10.1182/blood-2011-09-377846

DO - 10.1182/blood-2011-09-377846

M3 - Article

C2 - 22452979

AN - SCOPUS:84861215287

VL - 119

SP - 4686

EP - 4697

JO - Blood

JF - Blood

SN - 0006-4971

IS - 20

ER -