SGLT2 and cancer
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INVITED REVIEW
SGLT2 and cancer Ernest M. Wright 1 Received: 25 June 2020 / Revised: 6 August 2020 / Accepted: 10 August 2020 # The Author(s) 2020
Abstract Glycolysis plays a central role in tumor metabolism and growth, and this is reflected in a high rate of glucose uptake. It is commonly assumed that the upregulation of the facilitated glucose transporter GLUT1 meets the tumor’s demand for sugar. This underlies the success in using 2FDG PET imaging in the clinic to identify and stage many tumors. However, 2FDG is not a substrate for a second class of glucose transporters, the sodium-dependent glucose cotransporters, SGLTs, and so 2FDG PET may not provide a complete picture. A specific new radiotracer to detect SGLT activity has been introduced, Me4FDG, and this provides an opportunity to explore the potential role of SGLTs in supporting tumor glycolysis. In this brief review, I highlight the development of Me4FDG and our preliminary studies of Me4FDG PET in cancer patients. We find that the renal isoform, SGLT2, is expressed in pancreatic and prostate tumors and glioblastomas, and Me4FDG PET introduces a new method to image tumors. As SGLT2 drugs are successful in treating type 2 diabetes mellitus, they may also provide a new therapy. Keywords SGLT2 . Glioblastoma . PET . Inhibitors
Introduction Tumors require glucose to support their high rate of glycolysis to fuel their metabolism, growth, and proliferation. In vitro experiments have shown that withdrawing glucose or inhibiting glycolysis reduces cell proliferation and tumorigenesis. The increased cellular demand for glucose has been linked to the overexpression of the glucose transporter GLUT1 in the SLC2A gene family [4]. This has been exploited to image and stage tumors using 2FDG (2-[18F]-2deoxy-D-glucose) and positron emission tomography (PET) to image [14]. PET is a noninvasive imaging method that permits high temporal and spatial resolution of 18F-labeled tracers in animal and human subjects. 2FDG enters tumors through GLUTs, where it is accumulated after conversion to 2FDG-6-phosphate by intracellular hexokinase. Although it has been envisaged that GLUT1 inhibitors could be used to block tumor growth, this has not advanced owing to the fact that GLUT1 is essential in the supply of glucose to the brain. This article is part of the special issue on Glucose Transporters in Health and Disease in Pflügers Archiv—European Journal of Physiology * Ernest M. Wright [email protected] 1
Physiology Department, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1751, USA
Another challenge is that there are 14 genes in the human GLUT gene family SLC2, and specific isoform specific inhibitors have not yet come to market [13]. The cancer field has been slow to recognize that there is a second class of human glucose transporters, the sodiumcoupled transporters, SGLTs in the SLC5 gene family [11, 22, 24]. It is well known that SGLTs are important in intestinal glucose absorption and glucose reabsorption from the glomerular filtrate in the renal prox
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