Protein tyrosine phosphatase inhibition induces anti-tumor activity: evidence of Cdk2/p27 kip1 and Cdk2/SHP-1 complex formation in human ovarian cancer cells.
The protein tyrosine phosphatase (PTP) superfamily of enzymes functions with protein tyrosine kinases to regulate a broad spectrum of fundamental physiological processes. Addition of the PTP inhibitor potassium bisperoxo(1,10-phenanthroline)oxo-vanadate(V) [bpV(phen)] to the culture medium of human ovarian cancer cells (OVCAR-3) resulted in a dose-dependent decrease in the formation of tumors in a 3-D culture system. An evaluation of the potency of bpV(phen) in vivo confirmed the anti-tumor activity. Further study of the mechanism of action revealed a 40% decrease in Cdk2 kinase activity, an elevated level of Cdk2/p27(kip1), and the appearance of Cdk2/SHP-1 complexes. Therefore, a cytostatic dose of a PTP inhibitor increases the intracellular levels of Cdk2/p27(kip) and Cdk2/SHP-1 complexes, which indicate the presence of additional mechanisms underlying the anti-tumor activity.
Caron
Danielle
D
Department of Pediatrics, CRCHUL (CHUQ) Research Centre and Faculty of Medicine, Pediatric Research Unit, Laval University, 2705 Boulevard Laurier, RC-9800, Que., Canada.
Savard
Pierre E
PE
Doillon
Charles J
CJ
Olivier
Martin
M
Shink
Eric
E
Lussier
Jacques G
JG
Faure
Robert L
RL
D000230:Adenocarcinoma / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D018929:Cell Culture Techniques; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D009942:Organometallic Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010618:Phenanthrolines / Q000494:pharmacology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
C109198:CIB1 protein, human; D002135:Calcium-Binding Proteins; D009942:Organometallic Compounds; D010618:Phenanthrolines; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases