Selenate induces epithelial-mesenchymal transition in a colorectal carcinoma cell line by AKT activation.

Abstract

In addition to potent anticancer effects of selenite, a modest therapeutic effect of sodium selenate has been demonstrated in prostate cancer patients. Selenate acts by activating protein phosphatase 2A, which inhibits various signal transduction cascades, including the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The human colorectal carcinoma cell line DLD-1 harbors a constitutive active mutation in PIK3CA encoding the PI3K p110α catalytic subunit. Thus, we examined the anticancer effect of sodium selenate in DLD-1 cells. As expected, selenate significantly decreased cell viability and increased apoptosis at a 50% inhibitory concentration (IC50) of 0.88mM, whereas selenite was much more potent at an IC50 of 0.0061mM. Surprisingly, at lower concentrations (0.04-0.16mM), selenate induced changes in cell morphology and motility that are characteristic of the epithelial-mesenchymal transition (EMT). Moreover, selenate-induced EMT was associated with AKT activation, increased expression of the EMT-inducing transcription factor TWIST1 and the mesenchymal cell-specific intermediate filament vimentin, and decreased expression of the epithelial cell-specific adhesion molecule E-cadherin. The critical role of AKT activation in selenate-induced EMT was identified using the AKT inhibitor Akti-1/2, which suppressed EMT-associated cell motility and invasion. These results suggest that although sodium selenate is a potential anticancer drug, deleterious effects of EMT induction should be taken into careful consideration.

• Authors: Takanori Tsukamoto, Susumu Hama, Kentaro Kogure, Hiroyuki Tsuchiya
• Journal: Experimental cell research (Exp Cell Res) Vol. 319 Issue 13 Pg. 1913-1921 (Aug 01 2013) ISSN: 1090-2422 [Electronic] United States
• PMID: 23769801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Selenium Compounds
• Oncogene Protein v-akt
• Selenic Acid

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects, physiology)
• Epithelial-Mesenchymal Transition (drug effects)
• Humans
• Oncogene Protein v-akt (metabolism, physiology)
• Osmolar Concentration
• Selenic Acid
• Selenium Compounds (pharmacology)
• Up-Regulation (drug effects)