p27/Kip1 mediates retinoic acid-induced suppression of ovarian carcinoma cell growth.
We have investigated the mechanisms by which all-trans retinoic acid (ATRA) causes growth inhibition of ovarian carcinoma cells. As a model, we have studied the CAOV3 cell line, which is sensitive to ATRA, and the SKOV3 cell line, which is resistant. We have found that treatment of CAOV3 cells with ATRA causes a 5-10 fold increase in the protein level of the cyclin dependent kinase inhibitor p27/Kip1. p27/Kip1 protein upregulation is important in ovarian carcinoma as primary tumors are frequently found lacking this protein. The increase in p27/Kip1 is detected by day 3 of ATRA treatment of CAOV3 cells, and is maximal by day 5. Messenger RNA levels of p27/Kip1 do not change in CAOV3 cells following ATRA treatment, however, we have shown that p27/Kip1 mRNA is more stable in ATRA treated CAOV3 cells. Conversely, the ATRA resistant cell line SKOV3 fails to show p27/Kip1 accumulation. Interestingly, the SCF component protein SKP2 appears to be decreased in CAOV3 cells treated with ATRA. We have also shown that the ATRA dependent increase in p27/kip1 protein in CAOV3 cells leads to a decrease in the kinase activity of cyclin dependent kinase 4 (CDK4) following ATRA treatment. Finally, we found that CAOV3 cells stably transfected with a p27/kip1antisense construct, which express lower levels of p27/kip1 following ATRA treatment, and have a higher CDK4 kinase activity are less sensitive to ATRA induced growth suppression. Taken together our data suggest ATRA-induced growth inhibition in CAOV3 ovarian carcinoma cells involves modulation of the CDK inhibitor p27/kip1.
Vuocolo
Scott
S
Department of Microbiology & Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Soprano
Dianne Robert
DR
Soprano
Kenneth J
KJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D044786:S-Phase Kinase-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
D000970:Antineoplastic Agents; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D044786:S-Phase Kinase-Associated Proteins; C413374:p27 antigen; D014212:Tretinoin; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases