Glucose deprivation in tuberous sclerosis complex-related tumors

• Main Authors: Jiang Xiuyun, Kenerson Heidi L, Yeung Raymond S
• Format: Article
• Language: English
• Published: BMC 2011-10-01
• Series: Cell & Bioscience
• Subjects: mTOR; 2-deoxyglucose; glycolysis; metabolism; rapamycin; ketone bodies; fatty acids
• Online Access: http://www.cellandbioscience.com/content/1/1/34

<p>Abstract</p> <p>Background</p> <p>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 <it>in vitro</it>, but this concept has not been tested <it>in vivo</it>. This study examines the effects of restricting glucose metabolism by pharmacologic and dietary means in a tuberous sclerosis complex (TSC) tumor xenograft model.</p> <p>Results</p> <p>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 <it>Tsc2</it>-/- cells <it>in vitro</it>, 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.</p> <p>Conclusions</p> <p>Our data support the concept of glycolytic inhibition as a therapeutic approach in TSC whereas dietary withdrawal of carbohydrates was not effective.</p>