Glucose deprivation in tuberous sclerosis complex-related tumors

Cell & Bioscience

Raymond S Yeung¹  Heidi L Kenerson¹  Xiuyun Jiang¹ 

[1] Department of Surgery, University of Washington, Seattle, WA 98195, USA

关键词: fatty acids;    ketone bodies;    rapamycin;    metabolism;    glycolysis;    2-deoxyglucose;    mTOR;   

Others  :  793814
DOI  :  10.1186/2045-3701-1-34

 received in 2011-06-03, accepted in 2011-10-21,  发布年份 2011

【 摘 要 】

Background

Cancer 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.

Results

Tumor-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.

Conclusions

Our data support the concept of glycolytic inhibition as a therapeutic approach in TSC whereas dietary withdrawal of carbohydrates was not effective.

【 授权许可】

   
2011 Jiang et al; licensee BioMed Central Ltd.

【 图 表 】

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