Abstract
BackgroundCancer cells possess unique metabolic phenotypes that are determined by their underlying oncogenic pathways. Activation of the PI3K/Akt/mTOR signaling cascade promotes glycolysis and leads to glucose-dependence in tumors. In particular, cells with constitutive mTORC1 activity secondary to the loss of TSC1/TSC2 function are prone to undergo apoptosis upon glucose withdrawal in vitro, but this concept has not been tested in vivo. This study examines the effects of restricting glucose metabolism by pharmacologic and dietary means in a tuberous sclerosis complex (TSC) tumor xenograft model.ResultsTumor-bearing mice were randomly assigned to receive unrestricted carbohydrate-free ("Carb-free") or Western-style diet in the absence or presence of 2-deoxyglucose (2-DG) in one of four treatment groups. After 14 weeks, tumor sizes were significantly different among the four treatment groups with those receiving 2-DG having the smallest tumors. Unexpectedly, the "Carb-free" diet was associated with the largest tumors but they remained responsive to 2-DG. PET imaging showed significant treatment-related changes in tumor 18fluorodeoxyglucose-uptake but the standard uptake values did not correlate with tumor size. Alternative energy substrates such as ketone bodies and monounsaturated oleic acid supported the growth of the Tsc2-/- cells in vitro, whereas saturated palmitic acid was toxic. Correspondingly, tumors in the high-fat, "Carb-free" group showed greater necrosis and liquefaction that contributed to their larger sizes. In contrast, 2-DG treatment significantly reduced tumor cell proliferation, increased metabolic stress (i.e., ketonemia) and AMPK activity, whereas rapamycin primarily reduced cell size.ConclusionsOur data support the concept of glycolytic inhibition as a therapeutic approach in TSC whereas dietary withdrawal of carbohydrates was not effective.
Highlights
Cancer cells possess unique metabolic phenotypes that are determined by their underlying oncogenic pathways
Tuberous sclerosis is an autosomal dominant disorder characterized by multiple benign hamartomas and neoplasms caused by the disruption of a pair of tumor suppressor genes, TSC1 and TSC2, which encode for hamartin and tuberin, respectively [1]
Sensitivity of Tsc2-/- cells to 2-DG Our Tsc2-null tumor xenograft model utilizes tumorigenic LEF2 cells derived from an Eker rat renal tumor [27]
Summary
Cancer cells possess unique metabolic phenotypes that are determined by their underlying oncogenic pathways. This study examines the effects of restricting glucose metabolism by pharmacologic and dietary means in a tuberous sclerosis complex (TSC) tumor xenograft model. Tuberous sclerosis is an autosomal dominant disorder characterized by multiple benign hamartomas and neoplasms caused by the disruption of a pair of tumor suppressor genes, TSC1 and TSC2, which encode for hamartin and tuberin, respectively [1]. MTORC1 is constitutively activated in cells lacking TSC1 or TSC2. These findings led to the use of rapamycin and its analogs in the treatment of TSC and related disorders [8,9,10,11]. Long-term rapamycin can cause significant side effects, alternative approaches are being investigated
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