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Activation of phospholipase C induces the expression of the multidrug resistance (MDR1) gene through the Raf-MAPK

J M Yang1, A D Vassil, W N Hait

  • 1The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA. jyang@umdnj.edu

Molecular Pharmacology
|September 20, 2001
PubMed

Insights

Phospholipase C (PLC) activation regulates the multidrug resistance gene (MDR1) expression through the Raf-MAPK pathway. This discovery offers new insights into cancer drug resistance mechanisms.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • P-glycoprotein, encoded by the MDR1 gene, mediates resistance to multiple cancer chemotherapeutic drugs.
  • Various stimuli, including growth factors and heat shock, increase MDR1 gene expression.
  • Phospholipase C (PLC) activation is a common signaling pathway for many MDR1 gene expression regulators.

Purpose of the Study:

  • To investigate the role of PLC-mediated signaling in regulating MDR1 gene expression.
  • To identify the specific signaling pathway involved in PLC-induced MDR1 expression.

Main Methods:

  • Transfection of NIH 3T3 cells with PLC-gamma 1 expression vectors.
  • Reporter gene assays to measure MDR1 promoter activity.
  • Treatment with growth factors, kinase inhibitors (PD-98059, U0126), and expression vectors for Raf proteins.
  • Northern blot analysis of MDR1 mRNA levels in human renal carcinoma cells.

Main Results:

  • PLC-gamma 1 transfection increased MDR1 promoter activity 2- to 10-fold, requiring a specific promoter region (-106 to -99).
  • Platelet-derived growth factor enhanced PLC-mediated MDR1 promoter activity.
  • The Raf-MAPK pathway was activated by PLC, and its inhibition blocked PLC-induced MDR1 expression.
  • Activation of PLC by heat shock and growth factors increased endogenous MDR1 mRNA in human renal carcinoma cells, effects blocked by PLC-MAPK inhibitors.

Conclusions:

  • PLC activation by diverse cellular stimuli regulates MDR1 gene expression.
  • The Raf-MAPK pathway is essential for the transcriptional modulation of MDR1 expression by PLC.
  • These findings elucidate a key mechanism underlying multidrug resistance in cancer.

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