310 - Knocking Down Delta-5 Desaturase and Exploiting High Expression Level of COX-2 to Inhibit Cancer Migration and Invasion

Abstract

Our recent research has shown that knockdown of delta-5 desaturase (D5D, a key enzyme that converts dihomo-γ-linolenic acid to arachidonic acid) and treatment dihomo-γ-linolenic exerted growth inhibitory effect on both colon and pancreatic cancer cells (Xu Y et al, FRBM 96: 67-77, 2016 and Yang X et al, FRBM 97: 342-350, 2016) due to formation of an anti-cancer byproduct 8-hydroxyoctanoic acid (8-HOA) from COX-catalyzed peroxidation. Here, we further tested whether knockdown of D5D could also be used to inhibit cancer migration and invasion using colon cancer cell line HCA-7 colony 29 and pancreatic cancer cell line BxPC-3 (both express high levels of COX-2). Cell migration and invasion were assessed by wound healing assay and transwell assay along with western blot to investigate the possible molecular mechanism. Our results showed that promoted 8-HOA formation in cancer cells via knocking down D5D (shRNA transfection) can significantly inhibit cell migration. D5D knockdown can also significantly improve the efficacies of 5-flurouracil and gemcitabine on colon and pancreatic cancer cell migration and invasion. The underlying mechanism might be that 8-HOA, serving as histone deacetylase inhibitor, downregulates MMP-2 and 9, consequently leading to altered expression in key proteins involved in epithelial mesenchymal transition (EMT) e.g. E-cadherin and vimentin. For the first time, we demonstrated high COX expression in cancers could be taken advantage to inhibit cancer cell migration and invasion. The research outcome may provide us a promising strategy for cancer metastasis by taking advantage of abundant ω-6 fatty acids in daily diet and exploiting the high COX expression level in cancer (a paradigm shifting concept). This work supported by NIH R15CA195499 and Sanford Health-NDSU Collaborative Research Seed Grant Program.