In vitro growth inhibition of mouse mammary epithelial tumor cells by methylseleninic acid: involvement of protein kinases.
Methylseleninic acid (MSeA) is a synthetic organoselenium form known to be effective against mammary carcinogenesis in vivo. Using the synchronized mouse mammary epithelial tumor cell (TM6) model, we have previously shown that 5 microM MSeA significantly inhibits cell growth and induces a reversible growth arrest in the G1 phase. In the present study, we examined the effects of MSeA on Rb, cyclin dependent kinase 2 (cdk2), cdk4, cyclin E and cyclin D1. Growth arrest of cells was accompanied by a reduction in total cdk2 kinase and cyclin E-associated cdk2 kinase activities. The p27 levels associated with cdk2 were elevated during the cell cycle. In addition, growth inhibition correlated with a relative increase in the hypophosphorylated form of Rb in MSeA-treated cells and Egr1 was elevated in MSeA-treated cells. The Kinetworks Protein Kinase Screen (KPKS 1.0) was used to examine 75 protein kinases. MSeA treatment resulted in differential expression of several protein-serine/threonine kinases, protein-tyrosine kinases and protein-threonine/tyrosine kinases. Some of these kinases are being reported for the first time as being altered by MSeA. The outcome of these experiments will be of significance since these kinases are known to be involved in survival and/or apoptotic pathways of tumor cells.
Singh
Uma
U
Department of Pathology and Lab Medicine, UC Davis Medical Center, Sacramento, CA, USA.
Null
Kevin
K
Sinha
Raghu
R
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000187:drug effects / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000187:drug effects / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D015674:Mammary Neoplasms, Animal / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D016566:Organoselenium Compounds / Q000627:therapeutic use*
D009363:Neoplasm Proteins; D016566:Organoselenium Compounds; C008493:methylselenic acid; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4