Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α
Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α
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DOI：
10.1073/pnas.1312570111
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发表时间：
2014-02-18
影响因子：
11.1
通讯作者：
Jones, Russell G.
中科院分区：
文献类型：
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作者：
Faubert, Brandon;Vincent, Emma E.;Jones, Russell G.
与细胞转化相关的主要代谢变化之一是增强的营养利用，这通过促进能量产生和提供生长的生物合成中间体来支持肿瘤进展。肝激酶B1（LKB 1）是一种丝氨酸/苏氨酸激酶和肿瘤抑制剂，通过调节哺乳动物雷帕霉素靶蛋白（mTOR）活性将生物能量学与细胞生长控制偶联;然而，LKB 1对肿瘤代谢的影响尚未明确。在这里，我们表明，LKB 1的损失诱导增殖细胞中的促生长代谢程序。缺乏LKB 1的细胞显示葡萄糖和谷氨酰胺的摄取和利用增加，这支持细胞ATP水平和大分子生物合成增加。这种LKB 1依赖性细胞代谢重编程依赖于低氧诱导因子-1 α（HIF-1 α），其在LKB 1缺陷细胞中常氧下积累，并通过抑制mTOR复合物I信号传导而拮抗。沉默HIF-1 α逆转了LKB 1信号传导减少所带来的代谢优势，并损害了LKB 1缺陷肿瘤细胞在低营养条件下的生长和存活。总之，我们的数据表明肿瘤抑制因子LKB 1通过调节HIF-1 α依赖的代谢重编程作为肿瘤代谢和生长控制的中心调节因子。
One of the major metabolic changes associated with cellular transformation is enhanced nutrient utilization, which supports tumor progression by fueling both energy production and providing biosynthetic intermediates for growth. The liver kinase B1 (LKB1) is a serine/threonine kinase and tumor suppressor that couples bioenergetics to cell-growth control through regulation of mammalian target of rapamycin (mTOR) activity; however, the influence of LKB1 on tumor metabolism is not well defined. Here, we show that loss of LKB1 induces a progrowth metabolic program in proliferating cells. Cells lacking LKB1 display increased glucose and glutamine uptake and utilization, which support both cellular ATP levels and increased macromolecular biosynthesis. This LKB1-dependent reprogramming of cell metabolism is dependent on the hypoxia-inducible factor-1 alpha (HIF-1 alpha), which accumulates under normoxia in LKB1-deficient cells and is antagonized by inhibition of mTOR complex I signaling. Silencing HIF-1 alpha reverses the metabolic advantages conferred by reduced LKB1 signaling and impairs the growth and survival of LKB1-deficient tumor cells under low-nutrient conditions. Together, our data implicate the tumor suppressor LKB1 as a central regulator of tumor metabolism and growth control through the regulation of HIF-1 alpha-dependent metabolic reprogramming.