title: Protein kinases and multidrug resistance.
abstract: The role of protein kinases in the multidrug resistance phenotype of cancer cell lines is discussed with an emphasis on protein kinase C and protein kinase A. Evidence that P-glycoprotein is phosphorylated by these kinases is summarised and the relationship between P-glycoprotein phosphorylation and the multidrug-resistant phenotype discussed. Results showing that protein kinase C, particularly the alpha subspecies, is overexpressed in many MDR cell lines are described: this common but by no means universal finding seems to be drug- and cell line-dependent and in only in a few cases is there a direct correlation between protein kinase C activity and multidrug resistance. From co-immunoprecipitation results it is suggested that P-glycoprotein is a specific protein kinase C receptor, as well as being a substrate. Revertant experiments provide conflicting results as to a direct relationship between expression of P-glycoprotein and protein kinase C. Evidence that protein kinase A influences P-glycoprotein expression at the gene level is well documented and the mechanisms by which this occurs are becoming clarified. Results on the relationship between protein kinase C and multidrug resistance using many inhibitors and phorbol esters are difficult to interpret because such compounds bind to P-glycoprotein. In spite of huge effort, a direct involvement of protein kinase C in regulating multidrug resistance has not yet been firmly established. However, evidence that PKC regulates a Pgp-independent mechanism of drug resistance is accumulating.
authors.affiliation: Department of Biology, University of York, York, YO1 5YW, England., mgr1@york.ac.uk.
authors.forename: M G
authors.initials: MG
authors.lastname: Rumsby
authors.forename: L
authors.initials: L
authors.lastname: Drew
authors.forename: J R
authors.initials: JR
authors.lastname: Warr