GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling
Wen-Lian Chen, … , Wenyi Wei, Lijun Jia
Wen-Lian Chen, … , Wenyi Wei, Lijun Jia
Published February 13, 2020
Citation Information: JCI Insight. 2020;5(3):e131596. https://doi.org/10.1172/jci.insight.131596.
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Research Article Metabolism

GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling

Abstract

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 SLC2A5 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.

Authors

Wen-Lian Chen, Xing Jin, Mingsong Wang, Dan Liu, Qin Luo, Hechuan Tian, Lili Cai, Lifei Meng, Rui Bi, Lei Wang, Xiao Xie, Guanzhen Yu, Lihui Li, Changsheng Dong, Qiliang Cai, Wei Jia, Wenyi Wei, Lijun Jia

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Figure 9

Fructose utilization mediated by GLUT5 influences the activity of AMPK/mTORC1 signaling in LC.

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Fructose utilization mediated by GLUT5 influences the activity of AMPK/m...
(A) Phospho-protein profiling showing enhanced phosphorylation of AMPK and ACC1 and decreased phosphorylation of 4E-BP1, P70S6K, and S6 in A549 tumor xenograft with SLC2A5 deletion as relative to control A549 tumor xenograft. (B) Western blot approach validating the phosphorylation states of AMPK, ACC1, and 4E-BP1 between A549 tumor xenografts with SLC2A5 deletion and control A549 tumor xenografts. (C) RNA-Seq analysis showing repressed transcription of downstream target genes of mTORC1 signaling in A549 tumor xenografts with SLC2A5 abrogation. (D and E) Impact of fructose and glucose on AMPK (D) and 4E-BP1 (E) phosphorylation of A549 cells with or without SLC2A5 ablation. Control A549 cells and A549 cells with SLC2A5 deletion were starved in sugar-free medium for 2 hours and then were treated with 6 mM fructose or 6 mM glucose for 1 hour. Subsequently, cells were harvested for analysis. (F) The influence of an AMPK agonist, AICAR, on phosphorylation status of AMPK and 4E-BP1 in A549 cells cultured in fructose medium. Cells were treated with 1 mM AICAR or vehicle for 6 hours. Samples from the same batch were run at different times. The corresponding loading controls were shown for each measurement. (G) The influence of AICAR (1 mM) on proliferation of A549 cells cultured in fructose medium. Cumulative data were shown; n = 3. Data shown as mean ± SEM. **P < 0.01, 2-tailed Student’s t test.