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Post-transcriptional regulation of P-glycoprotein expression in cancer cell lines

Angeles Gómez-Martínez1, Pilar García-Morales, Alfredo Carrato

  • 1Instituto de Biología Molecular y Celular, Ed. Torregaitan, Universidad Miguel Hernández, 03202 Elche (Alicante), Spain.

Molecular Cancer Research : MCR
|June 21, 2007
PubMed

Insights

Histone deacetylase inhibitors increase P-glycoprotein (Pgp) mRNA but not Pgp protein in colon cancer cells, indicating translational control. Shorter MDR1 mRNA variants with altered 5' ends improve translation efficiency.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Histone deacetylase inhibitors are studied for cancer therapy.
  • P-glycoprotein (Pgp) is a key efflux pump in multidrug resistance.
  • MDR1 mRNA encodes Pgp, but its expression regulation is complex.

Purpose of the Study:

  • To investigate the regulation of P-glycoprotein (Pgp) expression in colon carcinoma cell lines.
  • To determine if histone deacetylase inhibitor-induced increases in MDR1 mRNA correlate with Pgp protein levels or activity.
  • To explore the role of mRNA structure and translation in Pgp expression.

Main Methods:

  • Analysis of Pgp mRNA, protein, and activity in colon carcinoma cell lines.
  • Polysome profile analysis to assess translational control.
  • Comparison of MDR1 mRNA size and 5' untranslated regions between different cell lines.

Main Results:

  • Histone deacetylase inhibitors increased MDR1 mRNA but not Pgp protein or activity in colon cancer cells.
  • Evidence of translational control of Pgp expression was observed.
  • MDR1 mRNA in colon cancer cells was shorter at the 5' end due to alternative promoter use.
  • Resistant cell lines with altered 5' untranslated regions showed improved MDR1 mRNA translational efficiency.

Conclusions:

  • Pgp expression in colon cancer cells is primarily regulated at the translational level, not solely by mRNA levels.
  • Alternative promoter usage generating shorter 5' untranslated regions in MDR1 mRNA can enhance translational efficiency and Pgp expression.
  • This finding offers insights into mechanisms of multidrug resistance and potential therapeutic strategies.

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