title: Overexpression of the RI alpha subunit of protein kinase A confers hypersensitivity to topoisomerase II inhibitors and 8-chloro-cyclic adenosine 3'5'-monophosphate in Chinese hamster ovary cells.
abstract: We have shown that a mutant derivative of Chinese hamster ovary CHO-K1 cells, ADR-5, which shows hypersensitivity to topoisomerase II (topo II)-inhibitory drugs, is cross-sensitive to the site-selective cyclic AMP analogue 8-chloro-cyclic AMP. We tested the hypothesis that overexpression of the type I alpha regulatory subunit of protein kinase A may represent a common element conferring hypersensitivity to both topo II inhibitors and 8-chloro-cyclic AMP in ADR-5 cells. We have demonstrated that ADR-5 cells overexpress RI alpha protein, compared to parental CHO-K1 cells. Moreover, retroviral vector-mediated transfer of the RI alpha gene into CHO-K1 cells was able to confer a drug-hypersensitive phenotype similar to that exhibited by ADR-5 cells. Analysis of topo II protein levels and activity revealed no differences between parental and infected cells, suggesting that protein kinase A may be involved in the downstream processing of topo II-mediated events.
authors.affiliation: Imperial Cancer Research Fund, Institute of Molecular Medicine, University of Oxford, United Kingdom.
authors.forename: P S
authors.initials: PS
authors.lastname: North
authors.forename: S L
authors.initials: SL
authors.lastname: Davies
authors.forename: F
authors.initials: F
authors.lastname: Ciardiello
authors.forename: V
authors.initials: V
authors.lastname: Damiano
authors.forename: C
authors.initials: C
authors.lastname: Bianco
authors.forename: S
authors.initials: S
authors.lastname: Pepe
authors.forename: A R
authors.initials: AR
authors.lastname: Bianco
authors.forename: A L
authors.initials: AL
authors.lastname: Harris
authors.forename: I D
authors.initials: ID
authors.lastname: Hickson
authors.forename: G
authors.initials: G
authors.lastname: Tortora
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology*; D016466:CHO Cells / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology*; D013713:Teniposide / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001761:Bleomycin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D005047:Etoposide; D013713:Teniposide; C044258:8-chloro-cyclic adenosine monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D002945:Cisplatin