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.
Highlights
Lung cancer (LC) is a highly lethal malignancy and results in the largest number of cancer-related deaths worldwide [1, 2]
When glucose level was low or deprived, tumor tissues significantly upregulated their fructose consumption rate, whereas nontumor tissues did not reveal this metabolic shift (Figure 1D). These findings suggested that fructose was an alternative carbon source and its metabolism was enhanced in LC tissues under glucose-limiting conditions, whereas matched adjacent normal lung tissues did not show this fructose-addicted feature
We demonstrate that circulating fructose is another crucial metabolic fuel for LC cells in vivo and that fructose utilization is strongly activated in LC tissues of patients under glucose-limited conditions
Summary
Lung cancer (LC) is a highly lethal malignancy and results in the largest number of cancer-related deaths worldwide [1, 2]. The most common type of LC is non-small cell lung cancer (85% of all LC), which is generally subcategorized into adenocarcinoma (ADC, 40% of all LC), squamous cell carcinoma (SCC, 25%–30% of all LC), and large cell carcinoma (10%–15% of all LC) [3]. Immune evasion in LC is focused on, and checkpoint inhibitor therapies are designed for patients with LC, especially for those without actionable driver mutations [5]. Despite these achievements, the 5-year survival rate in the LC population is still less than 20% [1, 2]. There is an increasing need to comprehensively understand the mechanisms involved in LC initiation and progression
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