Functional expression of sodium-glucose transporters in cancer

Contributed by Ernest M. Wright, June 16, 2015 (sent for review April 19, 2015; reviewed by Vadivel Ganapathy and Matthias A. Hediger)
July 13, 2015
112 (30) E4111-E4119

Significance

Cancers require high amounts of glucose to grow and survive, and dogma is that uptake is facilitated by passive glucose transporters (GLUTs). We have identified a new mechanism to import glucose into pancreatic and prostate cancer cells, namely active glucose transport mediated by sodium-dependent glucose transporters (SGLTs). This means that the specific radioactive imaging probe for SGLTs, α-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside, may be used along with positron-emission tomography to diagnose and stage pancreatic and prostate cancers, tumors in which the GLUT probe 2-[18F]fluoro-2-deoxy-d-glucose has questionable utility. Moreover, we suggest, based on our results in mouse models, that Food and Drug Administration-approved SGLT2 inhibitors may be used to reduce the viability of pancreatic and prostate cancer cells in patients.

Abstract

Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside (Me4FDG), which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy.

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Acknowledgments

We thank Drs. William McBride and Josephine Ratikan in Radiation Oncology for providing the NSG mice, training, and advice on establishing xenograft models, Ka Her for technical support, and Delia Adefuin for all her assistance in obtaining fresh tumor samples. We acknowledge Dr. Judy Gasson, Director of the UCLA Jonsson Comprehensive Cancer Center, and Dr. Sarah Dry, Director of the Center for Pathology Research Services, UCLA Department of Pathology and Laboratory Medicine, for their unfailing support of this project. C.S. was supported by a UCLA Scholars in Oncologic Molecular Imaging (SOMI) Fellowship and National Institutes of Health Grant R25 CA098010. This study was supported by grants from the National Institutes of Health (DK19567 and DK077133 to E.M.W.), the Elizabeth and Thomas Plott Endowed Chair in Gerontology (J.R.B.), and the UCLA Jonsson Comprehensive Cancer Center.

Supporting Information

Supporting Information (PDF)
Supporting Information
pnas.1511698112.sm01.mpg
pnas.1511698112.sm02.mpg
pnas.1511698112.sm03.mpg
pnas.1511698112.sm04.mpg

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 112 | No. 30
July 28, 2015
PubMed: 26170283

Classifications

Submission history

Published online: July 13, 2015
Published in issue: July 28, 2015

Keywords

  1. SGLT2
  2. pancreatic cancer
  3. prostate cancer
  4. SGLT2-inhibitors

Acknowledgments

We thank Drs. William McBride and Josephine Ratikan in Radiation Oncology for providing the NSG mice, training, and advice on establishing xenograft models, Ka Her for technical support, and Delia Adefuin for all her assistance in obtaining fresh tumor samples. We acknowledge Dr. Judy Gasson, Director of the UCLA Jonsson Comprehensive Cancer Center, and Dr. Sarah Dry, Director of the Center for Pathology Research Services, UCLA Department of Pathology and Laboratory Medicine, for their unfailing support of this project. C.S. was supported by a UCLA Scholars in Oncologic Molecular Imaging (SOMI) Fellowship and National Institutes of Health Grant R25 CA098010. This study was supported by grants from the National Institutes of Health (DK19567 and DK077133 to E.M.W.), the Elizabeth and Thomas Plott Endowed Chair in Gerontology (J.R.B.), and the UCLA Jonsson Comprehensive Cancer Center.

Authors

Affiliations

Claudio Scafoglio
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-6948;
Bruce A. Hirayama
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1751;
Vladimir Kepe
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-6948;
Jie Liu
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-6948;
Chiara Ghezzi
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1751;
Nagichettiar Satyamurthy
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-6948;
Neda A. Moatamed
Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
Jiaoti Huang
Department of Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
Hermann Koepsell
Institute for Anatomy and Cell Biology, University of Würzburg, 97070 Würzburg, Germany
Jorge R. Barrio1 [email protected]
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-6948;
Ernest M. Wright1 [email protected]
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1751;

Notes

1
To whom correspondence may be addressed. Email: [email protected] or [email protected].
Author contributions: C.S., B.A.H., J.R.B., and E.M.W. designed research; C.S., B.A.H., and C.G. performed research; J.L., N.S., and H.K. contributed new reagents/analytic tools; C.S., B.A.H., V.K., N.A.M., J.H., J.R.B., and E.M.W. analyzed data; and C.S., J.R.B., and E.M.W. wrote the paper.
Reviewers: V.G., Texas Tech University Health Science Center; and M.A.H., University of Bern.

Competing Interests

The authors declare no conflict of interest.

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    Functional expression of sodium-glucose transporters in cancer
    Proceedings of the National Academy of Sciences
    • Vol. 112
    • No. 30
    • pp. 9141-E4159

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