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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

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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 4

Abrogation of SLC2A5 impairs fructose uptake and fructose-induced cell proliferation of LC cells in vitro.

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Abrogation of SLC2A5 impairs fructose uptake and fructose-induced cell p...
(A) Western blot showing CRISPR/Cas9-mediated deletion of SLC2A5 in A549 and EKVX cells. (B) Fructose uptake by A549 and EKVX cells with or without SLC2A5 ablation in vitro. Statistical analysis was conducted using 1-way ANOVA test. After carrying out a homogeneity of variance test to confirm equal variance among subgroups, P values were acquired from post hoc test using LSD method. Cumulative data are shown; n = 3. (C) Fructose-induced cell proliferation of A549 and EKVX cells with or without SLC2A5 abrogation in vitro. Cells were cultured in fructose medium for 72 hours. Statistical analysis was conducted using 1-way ANOVA test. After performing a homogeneity of variance test to verify equal variance among subgroups, P values were gained from post hoc test using LSD method. Cumulative data are shown; n = 3. NC, nontarget control; KO, knockout. Data shown as mean ± SEM. ***P < 0.001, 2-tailed Student’s t test.

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