Helicobacter pylori VacA Reduces the Cellular Expression of STAT3 and Pro-survival Bcl-2 Family Proteins, Bcl-2 and Bcl-X^sub L^, Leading to Apoptosis in Gastric Epithelial Cells

• Published in: Digestive diseases and sciences Vol. 56; no. 4; p. 999
• Main Authors: Matsumoto, Ayako, Isomoto, Hajime, Nakayama, Masaaki, Hisatsune, Junzo, Nishi, Yoshito, Nakashima, Yujiro, Matsushima, Kayoko, Kurazono, Hisao, Nakao, Kazuhiko, Hirayama, Toshiya, Kohno, Shigeru
• Format: Journal Article
• Language: English
• Published: New York Springer Nature B.V 01-04-2011
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-010-1420-1

Helicobacter pylori vacuolating cytotoxin, VacA, stimulates apoptosis via a mitochondria-dependent pathway. VacA induces apoptosis via activation of the pro-apoptotic 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 pro-survival Bcl-2 family members as Bcl-2 and Bcl-X^sub L^ 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-X^sub L^. This study was conducted to elicit the implication of STAT3 and pro-survival Bcl-2 and Bcl-X^sub L^ in the intrinsic apoptosis. Immunoblot and reverse transcriptase real-time polymerase chain reaction (RT-PCR) were employed to assess the cellular expression of STAT3, Bcl-2, and Bcl-X^sub L^ 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. VacA reduced STAT3, Bcl-2, and Bcl-X^sub L^ expression in a dose-dependent manner. Knockdown of STAT3, Bcl-2, and Bcl-X^sub L^ 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 VacA-induced reduction of STAT3, Bcl-2, and Bcl-X^sub L^ expression. Instead, a c-JUN NH2-terminal kinase (JNK) inhibitor, SP600125, restored the VacA-induced reduction of STAT3 expression to the basal level. VacA-induced apoptosis may be, in part, implicated in the reduction of STAT3 linking to the downregulation of Bcl-2 and Bcl-X^sub L^, in association with JNK activity.[PUBLICATION ABSTRACT]