Helicobacter pylori VacA Reduces the Cellular Expression of STAT3 and Pro-survival Bcl-2 Family Proteins, Bcl-2 and Bcl-XL, Leading to Apoptosis in Gastric Epithelial Cells
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Ayako Matsumoto Hajime Isomoto Masaaki Nakayama Junzo Hisatsune Yoshito Nishi Yujiro Nakashima Kayoko Matsushima Hisao Kurazono Kazu
- چاپ و سال / کشور: 2010
Description
Background Helicobacter pylori vacuolating cytotoxin, VacA, stimulates apoptosis via a mitochondria-dependent pathway. VacA induces apoptosis via activation of the proapoptotic B-cell lymphoma (Bcl)-2 family proteins, Bcl- 2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), while the implication of such prosurvival Bcl-2 family members as Bcl-2 and Bcl-XL in the VacA-induced apoptosis remains unknown. Signal transduction and activator of transcription 3 (STAT3) is a pivotal transcription factor that upregulates Bcl-2 and Bcl-XL. Aims This study was conducted to elicit the implication of STAT3 and pro-survival Bcl-2 and Bcl-XL in the intrinsic apoptosis. Methods Immunoblot and reverse transcriptase real-time polymerase chain reaction (RT-PCR) were employed to assess the cellular expression of STAT3, Bcl-2, and Bcl-XL in response to purified VacA in gastric adenocarcinoma cell lines. VacA-induced apoptosis was quantitated morphologically following knockdown by each specific small interfering RNA (siRNA) or in the presence of pharmacological inhibitors. Results VacA reduced STAT3, Bcl-2, and Bcl-XL expression in a dose-dependent manner. Knockdown of STAT3, Bcl-2, and Bcl-XL by siRNA induced apoptosis to a similar extent in the case of sufficient VacA inoculation. The VacA-mediated reduction of STAT3 expression was independent of cellular vacuolization, since a vacuolar-type ATPase inhibitor, bafilomycin A1, did not inhibit VacAinduced reduction of STAT3, Bcl-2, and Bcl-XL expression. Instead, a c-JUN NH2-terminal kinase (JNK) inhibitor, SP600125, restored the VacA-induced reduction of STAT3 expression to the basal level. Conclusions VacA-induced apoptosis may be, in part, implicated in the reduction of STAT3 linking to the downregulation of Bcl-2 and Bcl-XL, in association with JNK activity.
Dig Dis Sci (2011) 56:999–1006 DOI 10.1007/s10620-010-1420-1 Received: 2 June 2010 / Accepted: 31 August 2010 / Published online: 7 October 2010
