title: Inhibition of aldose reductase prevents colon cancer metastasis.
abstract: Colon cancer is the third most common cause of cancer and is the second leading cause of cancer deaths in the USA. Although inhibition of aldose reductase (AR) is known to prevent human colon cancer cell growth in nude mice xenografts, the role of AR in the regulation of cancer metastasis is not known. We now demonstrate the mechanisms by which AR regulates colon cancer metastasis in vitro and in vivo. Inhibition of AR prevented the epidermal growth factor (EGF) or fibroblast growth factor (FGF)-induced migration and invasion of human colon cancer (HT29; KM20) cells by >70% and also inhibited (>80%) the adhesion of the cancer cells to endothelial cells. Treatment of endothelial cells with AR inhibitors significantly (∼85%) downregulated the EGF or FGF-induced expression of Inter-Cellular Adhesion Molecule-1, Vascular cell adhesion molecule-1 and vascular endothelial-cadherin. Furthermore, liver metastasis of green fluorescent protein-labeled KM20 cells injected into the spleen of athymic nude mice was significantly (>65%) prevented by AR inhibitor, fidarestat or ARsiRNA delivered systemically into the mice. Similar results were observed with HT29 cells. AR inhibition or ablation also prevented (70-90%) the increase in the levels of matrix metalloproteinase-2, cyclin D1, CD31, CD34 and the activation of nuclear factor-kappa-binding protein in metastatic liver. Thus, our results indicate that AR regulates cancer cell adhesion, invasion and migration events which initiate metastasis and therefore, AR inhibition could be a novel therapeutic approach for the prevention of colon cancer metastasis.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch,Galveston, TX 77555, USA.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Tammali
authors.forename: Aramati B M
authors.initials: AB
authors.lastname: Reddy
authors.forename: Ashish
authors.initials: A
authors.lastname: Saxena
authors.forename: Piotr G
authors.initials: PG
authors.lastname: Rychahou
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
authors.forename: Suimin
authors.initials: S
authors.lastname: Qiu
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.forename: Kota V
authors.initials: KV
authors.lastname: Ramana
authors.forename: Satish K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D048289:Imidazolidines / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D008114:Liver Neoplasms, Experimental / Q000201:enzymology* / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048289:Imidazolidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C077139:fidarestat; D000449:Aldehyde Reductase