Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein

Abstract

The multidrug resistance gene 1 (MDR1) product, P-glycoprotein (P-gp), pumps out a variety of anticancer agents from the cell, including anthracyclines, Vinca alkaloids, and taxanes. The expression of P-gp therefore confers resistance to these anticancer agents. In our present study, we found that FTI-277 (a farnesyltransferase inhibitor), U0126 [an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)], and 17-allylamino-17-demethoxygeldanamycin (an inhibitor of heat shock protein 90) reduced the endogenous expression levels of P-gp in the human colorectal cancer cells, HCT-15 and SW620-14. In contrast, inhibitors of phosphatidylinositol 3-OH kinase, mammalian target of rapamycin, p38 mitogen-activated protein kinase, and c-Jun NH 2 -terminal kinase did not affect P-gp expression in these cells. We further found that U0126 down-regulated exogenous P-gp expression in the MDR1-transduced human breast cancer cells, MCF-7/MDR and MDA-MB-231/MDR. However, the MDR1 mRNA levels in these cells were unaffected by this treatment. PD98059 (a MEK inhibitor), ERK small interfering RNA, and p90 ribosomal S6 kinase (RSK) small interfering RNA also suppressed P-gp expression. Conversely, epidermal growth factor and basic fibroblast growth factor enhanced P-gp expression, but the MDR1 mRNA levels were unchanged in epidermal growth factor -stimulated cells. Pulse-chase analysis revealed that U0126 promoted P-gp degradation but did not affect the biosynthesis of this gene product. The pretreatment of cells with U0126 enhanced the paclitaxel-induced cleavage of poly(ADP-ribose) polymerase and paclitaxel sensitivity. Furthermore, U0126-treated cells showed high levels of rhodamine123 uptake. Hence, our present data show that inhibition of the MEK-ERK-RSK pathway down-regulates P-gp expression levels and diminishes the cellular multidrug resistance.

Function of Aurora kinase A in Taxol-resistant breast cancer and its correlation with P-gp

“…The role of the ERK pathway in the generation of multidrug resistance has received more consideration than in the past. Previous studies demonstrated that the modulation of ERK activation may be a novel method used to reverse multidrug resistance (15). In the present study, the changing pattern of p-ERK was similar to that of p-Aurora A and P-gp; accordingly, p-Aurora A is proposed to regulate P-gp through p-ERK.…”

A traditional Chinese medicine formulation consisting of Rhizoma Corydalis and Rhizoma Curcumae exerts synergistic anti-tumor activity

“…It is well known that inhibition of the MEK-ERK-RSK pathway down-regulates P-gp expression levels and diminishes cellular multidrug resistance (24,28). Our studies demonstrated that ezhu and yanhusuo extracts exert a significant synergistic effect on inhibiting phosphorylation of ERK1/2 protein.…”

Triptolide exerts pro-apoptotic and cell cycle arrest activity on drug-resistant human lung cancer A549/Taxol cells via modulation of MAPK and PI3K/Akt signaling pathways

“…The development of MDR is often accompanied by the modulation of MAPKs (24)(25)(26). ERK1 and 2 are known to act as anti-apoptotic cascades by transducing survival signals, whereas JNK or p38 phosphorylation results in the promotion of apoptosis (27).…”