title: MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells.
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.
authors: Department of Clinical and Experimental Medicine, Gastroenterology Unit, Federico II University of Naples, Naples, Italy.
authors: Alba
authors: A
authors: Rocco
authors: Debora
authors: D
authors: Compare
authors: Eleonora
authors: E
authors: Liguori
authors: Alessandra
authors: A
authors: Cianflone
authors: Giuseppe
authors: G
authors: Pirozzi
authors: Virginia
authors: V
authors: Tirino
authors: Alessandra
authors: A
authors: Bertoni
authors: Margherita
authors: M
authors: Santoriello
authors: Corrado
authors: C
authors: Garbi
authors: Maria
authors: M
authors: D'Armiento
authors: Stefania
authors: S
authors: Staibano
authors: Gerardo
authors: G
authors: Nardone
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D037881:Aborted Fetus; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005756:Gastritis / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D020868:Gene Silencing / Q000187:drug effects; D016481:Helicobacter Infections / Q000150:complications / Q000378:metabolism; D016480:Helicobacter pylori; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D018613:Microscopy, Confocal / Q000379:methods; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000494:pharmacology; D013270:Stomach / Q000166:cytology; D013274:Stomach Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000628:therapy; D051020:bcl-X Protein / Q000276:immunology / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D051020:bcl-X Protein; C031192:oncofetal antigens