Se-methylselenocysteine inhibits phosphatidylinositol 3-kinase activity of mouse mammary epithelial tumor cells in vitro.
BACKGROUND
Se-methylselenocysteine (MSC), a naturally occurring selenium compound, is a promising chemopreventive agent against in vivo and in vitro models of carcinogen-induced mouse and rat mammary tumorigenesis. We have demonstrated previously that MSC induces apoptosis after a cell growth arrest in S phase in a mouse mammary epithelial tumor cell model (TM6 cells) in vitro. The present study was designed to examine the involvement of the phosphatidylinositol 3-kinase (PI3-K) pathway in TM6 tumor model in vitro after treatment with MSC.


METHODS
Synchronized TM6 cells treated with MSC and collected at different time points were examined for PI3-K activity and Akt phosphorylation along with phosphorylations of Raf, MAP kinase/ERK kinase (MEK), extracellular signal-related kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). The growth inhibition was determined with a [3H]thymidine incorporation assay. Immunoblotting and a kinase assay were used to examine the molecules of the survival pathway.


RESULTS
PI3-K activity was inhibited by MSC followed by dephosphorylation of Akt. The phosphorylation of p38 MAPK was also downregulated after these cells were treated with MSC. In parallel experiments MSC inhibited the Raf-MEK-ERK signaling pathway.


CONCLUSIONS
These studies suggest that MSC blocks multiple signaling pathways in mouse mammary tumor cells. MSC inhibits cell growth by inhibiting the activity of PI3-K and its downstream effector molecules in mouse mammary tumor cells in vitro.
Unni
Emmanual
E
Medicine Endocrinology, Baylor College of Medicine, Houston, Texas, USA. emmanual@bcm.tmc.edu
Koul
Dimpy
D
Yung
Wai-Kwan Alfred
WK
Sinha
Raghu
R
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D015674:Mammary Neoplasms, Animal / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017279:Selenocysteine / Q000031:analogs & derivatives; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017279:Selenocysteine; D048051:p38 Mitogen-Activated Protein Kinases; D003545:Cysteine; C002979:selenomethylselenocysteine