Functional expression of sodium-glucose transporters in cancer

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. 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.