Abstract 701: Loss of Krupple-like factor 10 enhanced epithelial-mesenchymal transition of pancreatic cancer by modulating glucose metabolism via Sirt 6 and PKM2

Abstract

Abstract Introduction: Pancreatic Cancer is well known for its deregulated TGFâ signaling. We have reported that the expression level of Krüpple like factor 10 (Klf10), a TGFâ early response transcription factor, is associated with clinical outcomes of pancreatic cancer patients. In this study, we would like to evaluate the mechanisms of Klf10 in promoting distant metastasis of pancreatic cancer. Materials and Methods: Klf10 over-expressing- or depleting-human pancreatic cancer cell lines were established. Western blot was used to evaluate epithelial-mesenchymal transition (EMT) markers and glycolysis related molecules. Cancer cell migration was measured by trans-well assay. Luciferase-labeled Panc-1 cells with or without Klf10 mRNA silencing were injected via tail veins of NOD/SCID mice to evaluate their metastatic ability. The glucose consumption, lactate production and mitochondrial respiration of pancreatic cancer cells were measured by assay kit or XFe Extracellular Flux Analyzers. Results: Down-regulating Klf10 in Panc-1 cells was associated with enhanced migration and invasion ability by in vitro and in vivo studies. Immunoblots of cell lysates revealed decreased expression level of E-cadherin and increased Twist, MMP9. Glycolysis activity was elevated while mitochondrial respiration decreased after silencing Klf10 mRNA in Panc-1 cells. The phenomenon was in parallel with decreased Sirt 6 and increased HIF-1á as well as PKM2 expression. We demonstrated that Klf10 bind to the promoter and transcriptionally regulated Sirt 6. Modulating Sirt 6 and PKM2 reversed the EMT and metastatic phenotype of Panc-1 cells with Klf10mRNA silencing. Discussion: Loss of Klf10 enhanced the migratory ability of pancreatic cancer cells. Klf10 transcriptionally regulated Sirt 6 which modulated glycolytic enzymes including PKM2 via HIF-1á. Elevated PKM2 promoted EMT phenotype and distant metastasis of pancreatic cancer. Klf10 is a potential prognostic and therapeutic biomarker for pancreatic cancer. Citation Format: Yi-Chih Tsai, Su-Liang Chen, HS Vincent Chang, Hui-Ju Ch’ang. Loss of Krupple-like factor 10 enhanced epithelial-mesenchymal transition of pancreatic cancer by modulating glucose metabolism via Sirt 6 and PKM2. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 701.