title: Protein tyrosine phosphatase inhibition induces anti-tumor activity: evidence of Cdk2/p27 kip1 and Cdk2/SHP-1 complex formation in human ovarian cancer cells.
abstract: 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.
authors.affiliation: Department of Pediatrics, CRCHUL (CHUQ) Research Centre and Faculty of Medicine, Pediatric Research Unit, Laval University, 2705 Boulevard Laurier, RC-9800, Que., Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Caron
authors.forename: Pierre E
authors.initials: PE
authors.lastname: Savard
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Doillon
authors.forename: Martin
authors.initials: M
authors.lastname: Olivier
authors.forename: Eric
authors.initials: E
authors.lastname: Shink
authors.forename: Jacques G
authors.initials: JG
authors.lastname: Lussier
authors.forename: Robert L
authors.initials: RL
authors.lastname: Faure
mesh_terms: 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
chemical_list: 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