Alteration of type II regulatory subunit of cAMP-dependent protein kinase in human cisplatin-resistant cells as a basis of collateral sensitivity to 8-chloro-cAMP.
A cyclic adenosine 3',5'-monophosphate (cAMP) analogue, 8-chloro-cAMP (8-Cl-cAMP), had a collateral growth-inhibitory effect on a cis-diamminedichloroplatinum(II) (CDDP)-resistant human cancer cell lines (PC-14/CDDP). The non-selective analogues dibutyryl-cAMP, 8-bromo-cAMP and forskolin, which are cAMP agonists, showed far less cytotoxicity than 8-Cl-cAMP in both cell lines. There was no significant difference in cAMP content between PC-14 and PC-14/CDDP. Because 8-Cl-cAMP has been shown to bind selectively to the site I receptor of the type II regulatory subunit (RII) of cAMP-dependent protein kinase, we determined the level of expression of regulatory subunits in PC-14 and PC-14/CDDP cells by photoaffinity labeling. PC-14/CDDP cells had a higher RII level, low site I receptor of type I regulatory subunit (RI) level, and a lower RI/RII ratio than the parental PC-14 cells. Exposure to 8-Cl-cAMP increased the RI and RII level in PC-14/CDDP cells in dose- and time-dependent manners. On the other hand, in parental PC-14 cells, RII was not detected and the levels of RI and RII were not increased by exposure to 8-Cl-cAMP. These results suggested that the change in RI and/or RII levels caused by 8-Cl-cAMP was correlated with 8-Cl-cAMP-induced growth inhibition and that the collateral sensitivity to 8-Cl-cAMP in CDDP-resistant cells was due to the increased RII level. Our results suggest that 8-Cl-cAMP can be used in combination with CDDP and that measurement of RI and RII levels and/or the RI/RII ratio is a useful tool to predict CDDP sensitivity.
Nishio
K
K
Pharmacology Division, National Cancer Center Research Institute, Tokyo.
Morikage
T
T
Kubota
N
N
Ohmori
T
T
Takeda
Y
Y
Fujiwara
Y
Y
Miki
K
K
Abe
K
K
Saijo
N
N
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004342:Drug Hypersensitivity / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D046911:Macromolecular Substances; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D046911:Macromolecular Substances; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D000242:Cyclic AMP; D011494:Protein Kinases; D002945:Cisplatin