MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Alba Rocco, Debora Compare, Eleonora Liguori, Alessandra Cianflone, Giuseppe Pirozzi, Virginia Tirino, Alessandra Bertoni, Margherita Santoriello, Corrado Garbi, Maria D'Armiento, Stefania Staibano, Gerardo Nardone

Research output: Contribution to journalArticlepeer-review

Abstract

P-glycoprotein (P-gp), traditionally linked to cancer poor prognosis and multidrug resistance, is undetectable in normal gastric mucosa and overexpressed in gastric cancer (GC). We propose that P-gp may be involved in Helicobacter pylori (Hp)-related gastric carcinogenesis by inhibiting apoptosis. Aim of the study was to evaluate the expression of P-gp in fetal stomach and in Hp-related gastric carcinogenesis, the epigenetic control of the multi-drug resistance-1 (MDR1) gene, the localization and interaction between P-gp and Bcl-x L and the effect of the selective silencing of P-gp on cell survival. P-gp and Bcl-xl expression was evaluated by immunohistochemistry on 28 spontaneously abortive human fetuses, 66 Hp-negative subjects, 138 Hp-positive chronic gastritis (CG) of whom 28 with intestinal metaplasia (IM) and 45 intestinal type GCs. P-gp/Bcl-x L colocalization was investigated by confocal immunofluorescence microscopy and protein-protein interaction by co-immunoprecipitation, in basal conditions and after stress-induced apoptosis, in GC cell lines AGS and MKN-28 and hepatocellular carcinoma cell line Hep-G2. The role of P-gp in controlling apoptosis was evaluated by knocking down its expression with a specific small interfering RNAs in stressed AGS and MKN-28 cell lines. P-gp is expressed in the gastric mucosa of all human fetuses while, it is undetectable in adult normal mucosa and re-expressed in 30/110 Hp-positive non-IM-CG, 28/28 IM-CG and 40/45 GCs. P-gp expression directly correlates with that of Bcl-x L and with the promoter hypomethylation of the MDR1 gene. In GC cell lines, P-gp is localized on the plasma membrane and mitochondria where it colocalizes with Bcl-x L. Co-immunoprecipitation confirms the physical interaction between P-gp and Bcl-x L in AGS, MKN-28 and Hep-G2, at both basal level and after stress-induced apoptosis. The selective silencing of P-gp sensitizes GC cells to stress-induced apoptosis. P-gp behaves as an oncofetal protein that, by cross-talking with Bcl-x L, acts as an anti-apoptotic agent in Hp-related gastric carcinogenesis.

Original languageEnglish
Pages (from-to)1407-1418
Number of pages12
JournalLaboratory Investigation
Volume92
Issue number10
DOIs
Publication statusPublished - Oct 2012

Keywords

  • apoptosis
  • gastric carcinogenesis
  • H. pylori
  • P-glycoprotein
  • stomach morphogenesis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

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