Most
cancer cells rely on aerobic glycolysis to support uncontrolled proliferation and evade apoptosis. However,
pancreatic cancer cells switch to
glutamine metabolism to survive under hypoxic conditions. Activation of the Wnt/β-
catenin pathway induces aerobic glycolysis by activating
enzymes required for
glucose metabolism and regulating the expression of glutamate transporter and
glutamine synthetase. The results demonstrate that
riluzole inhibits
pancreatic cancer cell growth and has no effect on human pancreatic normal ductal epithelial cells.
RNA-seq experiments identified the involvement of Wnt and metabolic pathways by
riluzole. Inhibition of Wnt-β-
catenin/TCF-LEF pathway by
riluzole suppresses the expression of PDK, MCT1, cMyc, AXIN, and CyclinD1.
Riluzole inhibits
glucose transporter 2 expression,
glucose uptake,
lactate dehydrogenase A expression, and NAD + level. Furthermore,
riluzole inhibits
glutamate release and
glutathione levels, and elevates
reactive oxygen species.
Riluzole disrupts mitochondrial homeostasis by inhibiting Bcl-2 and upregulating Bax expression, resulting in a drop of mitochondrial membrane potential. Finally,
riluzole inhibits
pancreatic cancer growth in KPC (Pdx1-Cre, LSL-Trp53R172H, and LSL-KrasG12D) mice. In conclusion,
riluzole can inhibit
pancreatic cancer growth by regulating
glucose and
glutamine metabolisms and can be used to treat
pancreatic cancer.