Protein kinases and multidrug resistance

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Multidrug resistance (MDR) is a major challenge in cancer chemotherapy.
• Protein kinases, including protein kinase C (PKC) and protein kinase A (PKA), are implicated in MDR.
• P-glycoprotein (P-gp) is a key efflux pump contributing to MDR.

Purpose of the Study:

• To review the role of PKC and PKA in the MDR phenotype of cancer cell lines.
• To summarize evidence linking P-gp phosphorylation by these kinases to MDR.
• To discuss the relationship between kinase activity/expression and MDR.

Main Methods:

• Literature review of studies investigating protein kinase involvement in MDR.
• Analysis of evidence for P-gp phosphorylation by PKC and PKA.
• Examination of co-immunoprecipitation and revertant experiments.
• Discussion of drug inhibitor and phorbol ester studies.

Main Results:

• PKA influences P-gp expression at the gene level, with clarifying mechanisms.
• PKC, particularly the alpha subspecies, is often overexpressed in MDR cell lines, but this is drug- and cell line-dependent.
• Co-immunoprecipitation suggests P-gp may be a specific PKC receptor and substrate.
• Direct correlation between PKC activity and MDR is not universally established, and some results are conflicting.
• Evidence for PKC regulating Pgp-independent drug resistance mechanisms is growing.

Conclusions:

• PKA has a documented role in regulating P-gp gene expression in MDR.
• The direct involvement of PKC in regulating MDR is not firmly established, despite extensive research.
• PKC may contribute to drug resistance through P-gp-independent pathways.