Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health-New Orleans, New Orleans, LA, 70122, USA.
Kansas City VA Medical Center, Kansas City, MO, 66128, USA.
Sci Rep. 2022 Jun 30;12(1):11062. doi: 10.1038/s41598-022-13472-y.
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-Trp53, and LSL-Kras) mice. In conclusion, riluzole can inhibit pancreatic cancer growth by regulating glucose and glutamine metabolisms and can be used to treat pancreatic cancer.
大多数癌细胞依赖有氧糖酵解来支持不受控制的增殖并逃避细胞凋亡。然而，胰腺癌细胞在缺氧条件下转而利用谷氨酰胺代谢来存活。Wnt/β-catenin 通路的激活通过激活葡萄糖代谢所需的酶和调节谷氨酸转运体和谷氨酰胺合成酶的表达来诱导有氧糖酵解。结果表明，利鲁唑抑制胰腺癌细胞生长，对人胰腺正常导管上皮细胞没有影响。RNA-seq 实验确定了利鲁唑对 Wnt 和代谢途径的参与。利鲁唑抑制 Wnt-β-catenin/TCF-LEF 通路，抑制 PDK、MCT1、cMyc、AXIN 和 CyclinD1 的表达。利鲁唑抑制葡萄糖转运蛋白 2 的表达、葡萄糖摄取、乳酸脱氢酶 A 的表达和 NAD+水平。此外，利鲁唑抑制谷氨酸释放和谷胱甘肽水平，并增加活性氧。利鲁唑通过抑制 Bcl-2 并上调 Bax 表达来破坏线粒体稳态，导致线粒体膜电位下降。最后，利鲁唑抑制 KPC（Pdx1-Cre、LSL-Trp53 和 LSL-Kras）小鼠中的胰腺癌细胞生长。总之，利鲁唑通过调节葡萄糖和谷氨酰胺代谢来抑制胰腺癌细胞生长，可用于治疗胰腺癌。
