P-GLYCOPROTEIN, MULTIDRUG-RESISTANCE AND PROTEIN-KINASE-C

The multidrug resistant (MDR) phenotype is a well-studied subject that has been recognized as a determinant underlying specific types of dru g resistance in human cancer, Although it is clear that the P-glycopro tein plays a major role in MDR, it is not clear whether post-translati onal modifications such as phosphorylation have any major impact on it s modulation. The laboratory of Dr. Bruce Chabner was one of the first to describe increased expression and activity of protein kinase C (PK C) associated with the MDR phenotype. Since that time, a similar corre lation has been observed in many other MDR cell lines, Most of these s tudies have been performed with doxorubicin-selected cells that have a cquired MDR and have shown increased PKC activity, mainly for PKC-alph a isoenzyme, Intrinsic MDR in human renal cell carcinoma lines has bee n shown to correlate directly with PKC activity, but further studies w ith intrinsic MDR cell lines are needed before any conclusions can be drawn. More recent evidence suggests that there is a complex biochemic al process by which PKC isoenzymes differentially phosphorylate specif ic serine residues in the linker region of P-glycoprotein which may le ad to alterations in P-glycoprotein ATPase and drug-binding functions, To further complicate matters, PKC plays an important role in anti-ap optotic pathways, which can confound the dissection and elucidation of drug-resistance mechanisms, However, these areas are still under acti ve investigation and not fully answered, Further studies are needed to specifically answer the question of whether PKC directly modulates ba sal and/or drug-stimulated P-glycoprotein function.