Fructose-Induced mTORC1 Activation Promotes Pancreatic Cancer Progression through Inhibition of Autophagy.

Excessive fructose intake is associated with the occurrence, progression, and poor prognosis of various tumors. A better understanding of the mechanisms underlying the functions of fructose in cancer could facilitate the development of better treatment and prevention strategies. In this study, we investigated the functional association between fructose utilization and pancreatic ductal adenocarcinoma (PDAC) progression. Fructose could be taken up and metabolized by PDAC cells and provided an adaptive survival mechanism for PDAC cells under glucose-deficient conditions. GLUT5-mediated fructose metabolism maintained the survival, proliferation, and invasion capacities of PDAC cells in vivo and in vitro. Fructose metabolism not only provided ATP and biomass to PDAC cells but also conferred metabolic plasticity to the cells, making them more adaptable to the tumor microenvironment. Mechanistically, fructose activated the AMP-activated protein kinase (AMPK)-mTORC1 signaling pathway to inhibit glucose deficiency-induced autophagic cell death. Moreover, the fructose-specific transporter GLUT5 was highly expressed in PDAC tissues and was an independent marker of disease progression in patients with PDAC. These findings provide mechanistic insights into the role of fructose in promoting PDAC progression and offer potential strategies for targeting metabolism to treat PDAC. Fructose activates AMPK-mTORC1 signaling to inhibit autophagy-mediated cell death in pancreatic cancer cells caused by glucose deficiency, facilitating metabolic adaptation to the tumor microenvironment and supporting tumor growth.