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.
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.
North
P S
PS
Imperial Cancer Research Fund, Institute of Molecular Medicine, University of Oxford, United Kingdom.
Davies
S L
SL
Ciardiello
F
F
Damiano
V
V
Bianco
C
C
Pepe
S
S
Bianco
A R
AR
Harris
A L
AL
Hickson
I D
ID
Tortora
G
G
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*
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