Protein kinases and multidrug resistance

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 k inase 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 c ell lines are described: this common but by no means universal finding seem s 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 resista nce. From co-immunoprecipitation results it is suggested that P-glycoprotei n is a specific protein kinase C receptor, as well as being a substrate. Re vertant experiments provide conflicting results as to a direct relationship between expression of P-glycoprotein and protein kinase C. Evidence that p rotein kinase A influences P-glycoprotein expression at the gene level is w ell documented and the mechanisms by which this occurs are becoming clarifi ed. Results on the relationship between protein kinase C and multidrug resi stance using many inhibitors and phorbol esters are difficult to interpret because such compounds bind to P-glycoprotein. In spite of huge effort, a d irect involvement of protein kinase C in regulating multidrug resistance ha s not yet been firmly established. However, evidence that PKC regulates a P gp-independent mechanism of drug resistance is accumulating.