Protein Kinase C Effectors Bind to Multidrug ABC Transporters and Inhibit Their Activity
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- 作者：Gwenaë ; lle Conseil ; José ; Maria Perez-Victoria ; Jean-Michel Jault ; Francisco Gamarro ; André ; Goffeau ; Johann Hofmann ; and Attilio Di Pietro
- 刊名：Biochemistry
- 出版年：2001
- 出版时间：February 27, 2001
- 年：2001
- 卷：40
- 期：8
- 页码：2564 - 2571
- 全文大小：112K
- 年卷期：v.40,no.8(February 27, 2001)
- ISSN：1520-4995
文摘
P-Glycoprotein and homologous multidrug transporters contain a phosphorylatable linkersequence that was proposed to control drug efflux on the basis that it was indeed phosphorylated in vitroand in vivo, and that inhibitors of protein kinase C (PKC) inhibited both P-glycoprotein phosphorylationand activity. However, site-directed mutagenesis of all phosphorylatable residues did not alter the drugresistance. The present work shows that PKC effectors are able to bind directly to multidrug transporters,from either cancer cells (mouse P-glycoprotein), yeast (Saccharomyces cerevisiae Pdr5p), or protozoanparasite (Leishmania tropica ltmdr1), and to inhibit their energy-dependent drug-efflux activity. The bindingof staurosporine and derivatives such as CGP 41251 is prevented by preincubation with ATP, suggestingat least partial interaction at the ATP-binding site. In contrast, more hydrophobic compounds such ascalphostin C and CGP 42700 bind outside the ATP-binding site and strongly interfere with drug interaction.A direct correlation is obtained between the efficiencies of PKC effectors to inhibit energy-dependentinteraction of rhodamine 6G with yeast Pdr5p, to promote intracellular drug accumulation in variousmultidrug resistant cells, and to chemosensitize growth of resistant cells. The noncompetitive inhibitionby PKC effectors of rhodamine 6G interaction with Pdr5p suggests that the binding might interfere withsignal transduction between nucleotide hydrolysis and drug interaction. The overall results indicate thatthe multidrug transporters from different species display common features for interaction with PKCinhibitors. The hydrophobic derivative of staurosporine, CGP 42700, constitutes a potentially powerfulmodulator of P-glycoprotein-mediated multidrug resistance.