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

• Published in: Laboratory investigation Vol. 92; no. 10; pp. 1407 - 1418
• Main Authors: Rocco, Alba, Compare, Debora, Liguori, Eleonora, Cianflone, Alessandra, Pirozzi, Giuseppe, Tirino, Virginia, Bertoni, Alessandra, Santoriello, Margherita, Garbi, Corrado, D'Armiento, Maria, Staibano, Stefania, Nardone, Gerardo
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.10.2012; Nature Publishing Group US; Nature Publishing Group
• Subjects: 631/45/612/1231; 631/80/82/23; 692/420/755; 692/699/1503/1504/1829; Aborted Fetus; Adult; Aged; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - immunology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; bcl-X Protein - immunology; bcl-X Protein - metabolism; Biological and medical sciences; Biomarkers, Tumor - immunology; Biomarkers, Tumor - metabolism; Biotechnology; Cell Line, Tumor; Cell Survival; DNA Methylation; Female; Fundamental and applied biological sciences. Psychology; gastric carcinogenesis; Gastric Mucosa - metabolism; Gastric Mucosa - pathology; Gastritis - metabolism; Gastritis - pathology; Gastritis - therapy; Gastroenterology. Liver. Pancreas. Abdomen; Gene Silencing - drug effects; H. pylori; Helicobacter Infections - complications; Helicobacter Infections - metabolism; Helicobacter pylori; Humans; Immunohistochemistry - methods; Immunoprecipitation - methods; Investigative techniques, diagnostic techniques (general aspects); Laboratory Medicine; Male; Medical sciences; Medicine; Medicine & Public Health; Metaplasia - metabolism; Metaplasia - pathology; Microscopy, Confocal - methods; Middle Aged; P-glycoprotein; Pathology; Promoter Regions, Genetic; research-article; RNA, Small Interfering - pharmacology; Stomach - cytology; stomach morphogenesis; Stomach Neoplasms - immunology; Stomach Neoplasms - metabolism; Stomach Neoplasms - microbiology; Stomach Neoplasms - therapy; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; P-glycoprotein; gastric carcinogenesis; apoptosis; H. pylori; stomach morphogenesis; Biotechnology; P Glycoprotein; Spirillaceae; H; Stomach cancer; Carcinogenesis; Morphogenesis; Helicobacter pylori; Clinical biology; Bacteria; Tumor cell; Gastric disease; Stomach; Cell survival; Spirillales; Digestive system; Malignant tumor; Protein; Cell death; MDR-1 gene; Digestive diseases; pylori; Cancer; Apoptosis
• ISSN: 0023-6837; 1530-0307; 1530-0307
• DOI: 10.1038/labinvest.2012.100

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-xL 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-xL 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-xL 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-xL. Co-immunoprecipitation confirms the physical interaction between P-gp and Bcl-xL 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-xL, acts as an anti-apoptotic agent in Hp-related gastric carcinogenesis.