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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 10

In vivo pharmacological blockage of fructose utilization by 2,5-AM ameliorates the malignancy of LC.

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In vivo pharmacological blockage of fructose utilization by 2,5-AM ameli...
(A and B) 2,5-AM treatment inhibited fructose uptake and fructose-1-phosphate generation in A549 (A) (n = 3 tumors for each group) and EKVX (B) (n = 5 tumors for each group) xenografts. (C and D) Subcutaneous tumor growth of A549 (C) and EKVX (D) cells treated with vehicle or 2,5-AM. (E and F) Heatmap showing the alteration of fatty acids in A549 (E) (n = 3 tumors for each group) and EKVX (F) (n = 5 tumors for each group) xenografts treated with 2,5-AM. (G) A model depicting that in vivo fructose utilization mediated by GLUT5 promotes LC growth. On the one hand, incorporated fructose is used to synthesize downstream fatty acids. On the other hand, fructose utilization activates the oncogenic AMPK/mTORC1 signaling pathway. This gives rise to a therapeutic opportunity by blocking fructose utilization using a GLUT5 inhibitor, 2,5-AM. Data shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed Student’s t test.

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