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 1

Activity of fructose utilization in LC tissues of patients.

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Activity of fructose utilization in LC tissues of patients. (A) Visualiz...
(A) Visualization of clinical parameters of enrolled patients in the study for metabolomic survey. ADC, n = 22; SCC, n = 13. TNM, extent of the primary tumor, involvement of lymph nodes, and distant metastases. (B and C) Concentrations of fructose and fructose-derived metabolites between paired adjacent normal lung tissues and tumor tissues from patients with lung ADC (n = 22) (B) or SCC (n = 13) (C). The midline represents the median of the data, with the upper and lower limits of the box being the third and first quartiles. Additionally, the whiskers of the box plot extend up to 1.5 times the interquartile range from the top or bottom of the box. P values were computed using 2-tailed Wilcoxon rank-sum test. Fructose-1-P, fructose-1-phosphate; DHAP, dihydroxyacetone phosphate. (D) Ex vivo study of fructose uptake between paired adjacent normal lung tissues (N) and tumor lung tissues (T) from patients with lung ADC or SCC. Tissues were cultured in complete medium containing 1.5 mM fructose and different levels of glucose for 48 hours. Statistical analysis was conducted using 1-way ANOVA test. After conducting a homogeneity of variance test to confirm equal variances among subgroups, P values were obtained from post hoc test using least significant difference (LSD) method. Cumulative data are shown; n = 3. Data shown as mean ± SEM; n = 3. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed Student’s t test.