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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 6

Enhanced fructose utilization via enforcing GLUT5 expression exacerbates the malignancy of LC xenografts.

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Enhanced fructose utilization via enforcing GLUT5 expression exacerbates...
(A) Western blot showing GLUT5 expression in A549 tumor xenografts with or without enforced GLUT5 expression. (B) 13C-fructose concentration in A549 xenografts with or without enforced GLUT5 expression (n = 5 tumors for each group). (C) Tumor growth of A549 xenografts with or without ectopic GLUT5 expression. (D) Xenograft images and tumor weight of A549 cells with or without ectopic GLUT5 expression (n = 10 tumors for each group). Scale bar: 1 cm. (E) Representative Western blot images exhibiting PCNA expression in A549 xenografts with or without enforced GLUT5 expression. Data shown as mean ± SEM. **P < 0.01; ***P < 0.001, 2-tailed Student’s t test.

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