title: 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.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Misasagi Nakauchi-cho 5, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Tsukamoto
authors.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Misasagi Nakauchi-cho 5, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Hama
authors.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Misasagi Nakauchi-cho 5, Yamashina-ku, Kyoto 607-8414, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kogure
authors.affiliation: Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Misasagi Nakauchi-cho 5, Yamashina-ku, Kyoto 607-8414, Japan. Electronic address: tutchyh@mac.com.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D051058:Oncogene Protein v-akt / Q000378:metabolism* / Q000502:physiology; D009994:Osmolar Concentration; D064586:Selenic Acid; D018036:Selenium Compounds / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D018036:Selenium Compounds; D051058:Oncogene Protein v-akt; D064586:Selenic Acid
keywords: 50% inhibitory concentration; AKT; AKT inhibitor; Akti-1/2; EMT; Epithelial–mesenchymal transition; IC(50); PI3K; PIP3; PP2A; PTEN; Protein phosphatase 2A; Sodium selenate; TWIST1; Vimentin; epithelial-mesenchymal transition; phosphatase and tensin homolog; phosphatidylinositol 3-kinase; phosphatidylinositol-3,4,5-trisphosphate; protein phosphatase 2A; qRT-PCR; quantitative reverse-transcription polymerase chain reaction