P‐Glycoprotein, Multidrug Resistance and Protein Kinase C

Abstract

Abstract. The multidrug resistant (MDR) phenotype is a well-studied subject that has been recognized as a determinant underlying specific types of drug resistance in human cancer. Although it is clear that the P-glycoprotein plays a major role in MDR, it is not clear whether post-translational modifications such as phosphorylation have any major impact on its modulation.The laboratory of Dr. Bruce Chabner was one of the first to describe increased expression and activity of protein kinase C (PKC) associated with the MDR phenotype. Since that time, a similar correlation has been observed in many other MDR cell lines. Most of these studies have been performed with doxorubicin-selected cells that have acquired MDR and have shown increased PKC activity, mainly for PKC-α isoenzyme. Intrinsic MDR in human renal cell carcinoma lines has been shown to correlate directly with PKC activity, but further studies with intrinsic MDR cell lines are needed before any conclusions can be drawn.More recent evidence suggests that there is a complex biochemical process by which PKC isoenzymes differentially phosphorylate specific serine residues in the linker region of P-glycoprotein which may lead to alterations in P-glycoprotein ATPase and drug-binding functions. To further complicate matters, PKC plays an important role in anti-apoptotic pathways, which can confound the dissection and elucidation of drug-resistance mechanisms. However, these areas are still under active investigation and not fully answered. Further studies are needed to specifically answer the question of whether PKC directly modulates basal and/or drug-stimulated P-glycoprotein function.This manuscript reviews the majority of the literature on PKC and MDR, as well as offers caveats for interpretation of these studies to answer the above questions.

Antisense expression of PKCalpha improved sensitivity of SGC7901/VCR cells to doxorubicin

“…Activation of PKC results in phosphorylation of Pgp and a decrease in drug accumulation, while inhibition of PKC can partially reverse the MDR phenotype [5,6] . PKC comprises a family of at least 12 distinct serine/ threonine kinase isoenzymes which are found in varying ratios in the cytosolic and membrane fractions of cells, depending on the type of issue and its physiological state [6,7] .…”

“…PKC comprises a family of at least 12 distinct serine/ threonine kinase isoenzymes which are found in varying ratios in the cytosolic and membrane fractions of cells, depending on the type of issue and its physiological state [6,7] . The family of PKC is composed of three subclasses: classical, novel and atypical PKC, each having different isoforms.…”

“…PKC regulates numerous cell processes including proliferation, apoptosis and differentiation by phosphorylating proteins in response to transmembrane signals from hormones, growth factors, neuro-transmitters and pharmacological agents [5] . Recently accumulated evidence indicated that PKC, especially classical PKC, plays a significant role in the formation of cancer MDR [5,6] . The isoenzymes of PKC possess distinct differences in localization in different cells, and research on distinct function of isoforms in cancer MDR has important significance [5,6] .…”

“…Recently accumulated evidence indicated that PKC, especially classical PKC, plays a significant role in the formation of cancer MDR [5,6] . The isoenzymes of PKC possess distinct differences in localization in different cells, and research on distinct function of isoforms in cancer MDR has important significance [5,6] . Among those isoforms of PKC, PKCα is likely to play a decisive role in maintaining MDR phenotypes in some cancer cells, and may therefore represent potential novel targets for the treatment of cancers [6,[8][9][10][11][12] .…”

Impact of BCRP/MXR, MRP1 and MDR1/P‐Glycoprotein on thermoresistant variants of atypical and classical multidrug resistant cancer cells

“…63 Data are available that particular protein kinase C isozymes might be involved in the up-regulation of a series of MDR-associated factors, such as MRP1, MDR-1/P-glycoprotein and lung resistance protein 64 and might contribute to a thermotolerant phenotype. 65 These findings indicate that there might be cellular factors that could play a role in the development of pleiotropic phenomena observed in the panel of drug-and thermoresistant cell variants derived from the human gastric carcinoma EPG85-257P.…”