GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling
GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling
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GLUT5 介导的果糖利用通过刺激脂肪酸合成和 AMPK/mTORC1 信号传导促进肺癌生长
DOI：
10.1172/jci.insight.131596
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发表时间：
2020-02-13
期刊：
影响因子：
8
通讯作者：
Jia, Lijun
中科院分区：
文献类型：
--
作者：
Chen, Wen-Lian;Jin, Xing;Jia, Lijun
肺癌（LC）是全球癌症相关死亡的主要原因。它的快速增长需要主要代谢燃料的过度活跃的催化剂。目前还不清楚果糖，目前饮食中丰富的糖，是否是LC所必需的。我们证明，在体内代谢燃料共存的条件下，果糖很容易被LC细胞在体内作为葡萄糖的替代品，通过上调GLUT 5，溶质载体家族2成员5（SLC2A5）编码的主要果糖转运蛋白。代谢组学分析与同位素示踪相结合表明，掺入的果糖被分解代谢以促进脂肪酸合成和棕榈油酸生成，特别是加速体内LC生长。在体外和体内补充棕榈油酸可以恢复由SLE2A5缺失引起的受损的LC增殖。此外，分子机制研究表明，GLUT 5介导的果糖利用需要抑制AMPK，从而激活mTORC 1活性，以促进LC生长。因此，使用GLUT 5抑制剂的体内果糖利用的药理学阻断显著地减少了LC生长。总之，这项研究强调了由GLUT 5介导的体内果糖利用在控制LC生长中的重要性，并强调了通过靶向GLUT 5来消除那些果糖成瘾的肿瘤细胞来治疗LC的有希望的策略。
Lung cancer (LC) is a leading cause of cancer-related deaths worldwide. Its rapid growth requires hyperactive catabolism of principal metabolic fuels. It is unclear whether fructose, an abundant sugar in current diets, is essential for LC. We demonstrated that, under the condition of coexistence of metabolic fuels in the body, fructose was readily used by LC cells in vivo as a glucose alternative via upregulating GLUT5, a major fructose transporter encoded by solute carrier family 2 member 5 (SLC2A5). Metabolomic profiling coupled with isotope tracing demonstrated that incorporated fructose was catabolized to fuel fatty acid synthesis and palmitoleic acid generation in particular to expedite LC growth in vivo. Both in vitro and in vivo supplement of palmitoleic acid could restore impaired LC propagation caused by SLE2A5 deletion. Furthermore, molecular mechanism investigation revealed that GLUT5-mediated fructose utilization was required to suppress AMPK and consequently activate mTORC1 activity to promote LC growth. As such, pharmacological blockade of in vivo fructose utilization using a GLUT5 inhibitor remarkably curtailed LC growth. Together, this study underscores the importance of in vivo fructose utilization mediated by GLUT5 in governing LC growth and highlights a promising strategy to treat LC by targeting GLUT5 to eliminate those fructose-addicted neoplastic cells.