Research ArticleCancer

Targeting GLUT1 and the Warburg Effect in Renal Cell Carcinoma by Chemical Synthetic Lethality

Science Translational Medicine  03 Aug 2011:
Vol. 3, Issue 94, pp. 94ra70
DOI: 10.1126/scitranslmed.3002394

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Cancer’s Achilles’ Heel

A quick tug on a fuel line can stop a car dead in its tracks. Similarly, depriving a cancer cell of its energy source can bring proliferation to a standstill. Chan et al. devised a drug discovery assay that took advantage of the fact that some kidney cancer cells depend on glucose for survival. By screening 64,000 small molecules, the authors found a class of drug that inhibits the glucose transporter and selectively impairs growth of these cancer cells in cultures and in animals.

Certain kidney and other types of cancer cells lack the von Hippel–Lindau (VHL) tumor suppressor protein. This deficiency reorients carbohydrate metabolism so that the cancer cells depend on aerobic glycolysis—the conversion of glucose to lactate—rather than the more typical oxidative phosphorylation for a supply of energy. The drug identified by the authors, STF-31, was toxic to the VHL-deficient kidney tumor cells but, unlike many other cancer drugs, did not induce autophagy, apoptosis, or DNA damage. Rather, STF-31 exploited the fact that inactivation of VHL increases the activity of hypoxia-inducible factor transcription factor, which in turn stimulates the transcription of genes involved in glucose metabolism, including the glucose transporter–encoding gene GLUT1. By binding directly to the transporter, STF-31 blocked glucose uptake in VHL-deficient cancer cells but not in those with intact VHL; with their sugar delivery system stymied, the tumor suppressor–deprived cancer cells ceased glycolysis and thus adenosine 5′-triphosphate production and succumbed to necrosis.

An extra benefit of the new agent is that its activity can be easily visualized, even deep inside an animal. Glucose uptake in a tumor can be monitored by fluorodeoxyglucose positron emission tomography. The reduction in glucose metabolism forced on tumors by STF-31 was detected in mice with this method—an approach that can be readily applied to humans to test the drug’s efficacy. If it can thwart the fuel supply line in human cancers, this promising drug likely will bring tumor thriving to a halt.


  • * These authors contributed equally to this work.

  • Citation: D. A. Chan, P. D. Sutphin, P. Nguyen, S. Turcotte, E. W. Lai, A. Banh, G. E. Reynolds, J.-T. Chi, J. Wu, D. E. Solow-Cordero, M. Bonnet, J. U. Flanagan, D. M. Bouley, E. E. Graves, W. A. Denny, M. P. Hay, A. J. Giaccia, Targeting GLUT1 and the Warburg Effect in Renal Cell Carcinoma by Chemical Synthetic Lethality. Sci. Transl. Med. 3, 94ra70 (2011).