Inhibition Of Colorectal Cancer Metastasis By Dapagliflozin Via The PI3K/AKT/mTOR Signaling Pathway

Background:Colorectal cancer metastasis is considered as a key influencer for colorectal cancer-related deaths.It was previously found that colorectal cancer patients with type 2 diabetes had a higher rate for colorectal cancer metastasis.In literature,Dapagliflozin,a new anti-diabetic agent,has been shown to inhibit the progression of several malignancies,including non-small cell lung cancer,while lowering patients'blood glucose levels.Till present,the significance of dapagliflozin in colorectal cancer not well-understood.Objective:This study aimed to explore the effect of dapagliflozin on inhibiting colorectal cancer metastasis to increase the efficacy of chemotherapy;which may provide a new theoretical basis for the clinical treatment of colorectal cancer with type 2 diabetes.Methods:The following experiments were performed:1.Wound healing Test and Transwell Test were performed to investigate the effect of dapagliflozin on the biological function of colorectal cancer cells.2.The efficacy of dapagliflozin on chemotherapeutic drugs such as fluorouracil(5-FU)and oxaliplatin was detected by the Chemotherapy Resistance Test.3.Subcutaneous tumor implantation model,the liver metastasis model of spleen-implanted model and cecum orthotopic implantation model in nude mice were used to observe the effect of dapagliflozin on colorectal cancer metastasis in vivo.4.The effect on EMT was verified by western blot and immunofluorescence experiments.5.Finally,by adding PI3K/AKT pathway activator SB-216763,the effect of dapagliflozin on PI3K/AKT/mTOR signaling pathway was verified by Transwell,wound healing test,Western blot and immunofluorescence experiments.Results:Our findings showed that:1.Dapagliflozin inhibited the invasion and metastasis of colorectal cancer in the Wound Healing Test and Transwell Test,in vitro.2.Chemotherapy Resistance Test indicated that dapagliflozin enhanced the sensitivity of colorectal cancer cells to the investigated chemotherapeutic agents.3.Spleen-implanted model and cecum orthotopic implantation model in nude mice demonstrated that dapagliflozin inhibited the invasion and metastasis of colorectal cancer in vivo.4.Western blot,HE,immunofluorescence and immunohistochemistry showed that dapagliflozin inhibited EMT and phosphorylation of the PI3K/AKT/mTOR signaling pathway in colorectal cancer.Conclusion:Dapagliflozin demonstrated the potential to inhibit the invasion and metastasis of colorectal cancer in vitro and in vivo by inhibiting the EMT process and the phosphorylation of the PI3K/AKT/mTOR signaling pathway.Further,it could be used as a combo to increase the sensitivity to chemotherapeutic agent such as 5-FU and oxaliplatin to enhance the patients treatment respons.