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-, 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.SGLT2 | pancreatic cancer | prostate cancer | SGLT2-inhibitors P ancreatic cancer is the fourth-leading cause of cancer-related death in the United States (behind only lung, colon, and breast cancers), with 46,420 estimated new cases in 2014 and a mortality that almost equals incidence (39,590 estimated deaths in 2014); the overall 5-y survival rate is only 7% (seer.cancer.gov/statfacts/html/ pancreas.html). Prostate cancer is the most frequent cancer in men in the United States, with 233,000 estimated new cases in 2014. Despite widespread adoption of screening programs, prostate cancer is still the second-leading cause of cancer-related death in men, second only to lung cancer (seer.cancer.gov/statfacts/html/prost.

Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule

“…This supports the previous indirect evidence provided by SGLT2 immunohistochemistry and gene expression. 9,[14][15][16] Therefore, for at least one SGLT2 inhibitor, dapagliflozin, we have obtained the direct evidence that the drug acts on the apical membrane of the early proximal tubule after glomerular filtration and then, is reabsorbed by the nephron back into blood. These rodent data are consistent with the clinical studies of SGLT2 drugs in healthy individuals and patients with type 2 diabetes and provide a scientific rational for the clinical observations on their specificity, mode of action, and apparent lack of adverse effects.…”

“…The distribution of F-Dapa grains over the mouse kidney closely mimics the distribution SGLT2 gene expression in rat kidney 14 and SGLT2 antibody binding to mouse, rat, and human kidneys. 9,15,16 There is no significant SGLT2 expression in these kidney glomeruli. …”

“…F-Dapa autoradiographic images of kidney slices show that F-Dapa is bound to the kidney with a pattern closely resembling the in situ hybridization of SGLT2 mRNA in the rat kidney 14 and SGLT2 antibody binding. 9,16 Higher magnification shows that F-Dapa silver grains are concentrated in tubules in the outer cortex and that at the highest magnification silver grains are concentrated in some but not all of the tubule sections close to glomeruli ( Figure 6C). These results suggest that F-Dapa is filtered at the glomerulus and binds to the apical membrane of early proximal tubules.…”

“…We have previously shown 6,9,10 that Me-4FDG in combination with microPET is a useful tool to study in vivo functional SGLT activity. To confirm that dapagliflozin specifically inhibited SGLT2, we measured the excretion of Me-4FDG into the urinary bladder of wild-type (WT) mice with or without injection of SGLT inhibitors.…”

Type 2 diabetes therapeutic strategies: why don't we see the «ELEPHANT» in the room?

“…В противоположность им, применение ингибиторов SGLT2 может оказывать значительное положительное влияние на пациентов с онкологическими заболевани-ями [22]. Безопасность в отношении сердечно-сосуди-…”