Department of Surgery, University of Washington, Seattle, WA 98195, USA.
Cell Biosci. 2011 Oct 21;1:34. doi: 10.1186/2045-3701-1-34.
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.
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.
Our data support the concept of glycolytic inhibition as a therapeutic approach in TSC whereas dietary withdrawal of carbohydrates was not effective.
癌细胞具有独特的代谢表型，这些表型是由其潜在的致癌途径决定的。PI3K/Akt/mTOR 信号级联的激活促进糖酵解，并导致肿瘤对葡萄糖的依赖性。特别是，由于 TSC1/TSC2 功能丧失而导致 mTORC1 活性持续存在的细胞在体外葡萄糖耗尽时容易发生凋亡，但这一概念尚未在体内得到验证。本研究通过药理和饮食手段限制葡萄糖代谢，在结节性硬化症（TSC）肿瘤异种移植模型中研究其效果。
荷瘤小鼠随机分为四组，分别接受无限制碳水化合物（“无碳水化合物”）或西式饮食，同时或不接受 2-脱氧葡萄糖（2-DG）治疗。14 周后，四组治疗组的肿瘤大小存在显著差异，接受 2-DG 治疗的肿瘤最小。出乎意料的是，“无碳水化合物”饮食与最大的肿瘤相关，但它们仍然对 2-DG 有反应。PET 成像显示肿瘤 18 氟脱氧葡萄糖摄取有显著的治疗相关变化，但标准摄取值与肿瘤大小无关。替代能量底物，如酮体和单不饱和油酸，支持 Tsc2-/-细胞在体外的生长，而饱和棕榈酸则具有毒性。相应地，高脂肪“无碳水化合物”组的肿瘤显示出更大的坏死和液化，这导致了它们更大的体积。相比之下，2-DG 治疗显著降低了肿瘤细胞的增殖，增加了代谢应激（即酮血症）和 AMPK 活性，而雷帕霉素主要降低了细胞大小。
我们的数据支持将糖酵解抑制作为 TSC 的治疗方法，而饮食中去除碳水化合物则无效。
