Functional expression of sodium-glucose transporters in cancer.

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-[(18)F]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.

• Authors: Claudio Scafoglio, Bruce A Hirayama, Vladimir Kepe, Jie Liu, Chiara Ghezzi, Nagichettiar Satyamurthy, Neda A Moatamed, Jiaoti Huang, Hermann Koepsell, Jorge R Barrio, Ernest M Wright
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 30 Pg. E4111-9 (Jul 28 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26170283 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorine Radioisotopes
• Glucose Transport Proteins, Facilitative
• Glucosides
• SLC5A2 protein, human
• Slc5a2 protein, mouse
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• methyl-4-fluoro-4-deoxyglucose

Topics

• Adenocarcinoma (metabolism)
• Animals
• Biological Transport
• Female
• Fluorine Radioisotopes (chemistry)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Glucose Transport Proteins, Facilitative (metabolism)
• Glucosides (chemistry)
• Humans
• Immunohistochemistry
• Kidney (metabolism)
• Male
• Mice
• Necrosis
• Neoplasm Transplantation
• Pancreatic Neoplasms (drug therapy, metabolism)
• Positron-Emission Tomography
• Prostatic Neoplasms (drug therapy, metabolism)
• Sodium-Glucose Transporter 2 (metabolism)
• Sodium-Glucose Transporter 2 Inhibitors