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

Kazuhiro Katayama, Sho Yoshioka, Satomi Tsukahara, Junko Mitsuhashi, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

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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 NH2-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.

Original languageEnglish
Pages (from-to)2092-2102
Number of pages11
JournalMolecular Cancer Therapeutics
Volume6
Issue number7
DOIs
Publication statusPublished - 2007 Jul 1

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P-Glycoprotein
Mitogen-Activated Protein Kinases
Down-Regulation
MDR Genes
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinase Kinases
tanespimycin
Paclitaxel
Epidermal Growth Factor
Antineoplastic Agents
Small Interfering RNA
90-kDa Ribosomal Protein S6 Kinases
Vinca Alkaloids
Ribosomal Protein S6 Kinases
Farnesyltranstransferase
MAP Kinase Kinase Kinases
HSP90 Heat-Shock Proteins
Taxoids
Messenger RNA
Poly(ADP-ribose) Polymerases

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein. / Katayama, Kazuhiro; Yoshioka, Sho; Tsukahara, Satomi; Mitsuhashi, Junko; Sugimoto, Yoshikazu.

In: Molecular Cancer Therapeutics, Vol. 6, No. 7, 01.07.2007, p. 2092-2102.

Research output: Contribution to journalArticle

Katayama, Kazuhiro ; Yoshioka, Sho ; Tsukahara, Satomi ; Mitsuhashi, Junko ; Sugimoto, Yoshikazu. / Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 7. pp. 2092-2102.
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