Helicobacter pylori VacA reduces the cellular expression of STAT3 and pro-survival Bcl-2 family proteins, Bcl-2 and Bcl-X L, leading to apoptosis in gastric epithelial cells

Ayako Matsumoto, Hajime Isomoto, Masaaki Nakayama, Junzo Hisatsune, Yoshito Nishi, Yujiro Nakashima, Kayoko Matsushima, Hisao Kurazono, Kazuhiko Nakao, Toshiya Hirayama, Shigeru Kohno

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Background: 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 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 L. Aims: This study was conducted to elicit the implication of STAT3 and pro-survival Bcl-2 and Bcl-X L 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-X 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. Results: VacA reduced STAT3, Bcl-2, and Bcl-X L expression in a dose-dependent manner. Knockdown of STAT3, Bcl-2, and Bcl-X 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 L expression. Instead, a c-JUN NH 2-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-X L, in association with JNK activity.

Original languageEnglish
Pages (from-to)999-1006
Number of pages8
JournalDigestive Diseases and Sciences
Volume56
Issue number4
DOIs
Publication statusPublished - Apr 2011
Externally publishedYes

Fingerprint

B-Lymphoid Precursor Cells
B-Cell Lymphoma
Helicobacter pylori
Signal Transduction
Stomach
Epithelial Cells
Apoptosis
IgA receptor
Small Interfering RNA
MAP Kinase Kinase 4
Vacuolar Proton-Translocating ATPases

Keywords

  • Apoptosis
  • B-cell lymphoma (Bcl)-2 and Bcl-X
  • c-JUN NH -terminal kinase, JNK
  • Signal transduction and activator of transcription 3, STAT3
  • Vacuolating cytotoxin, VacA

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

Helicobacter pylori VacA reduces the cellular expression of STAT3 and pro-survival Bcl-2 family proteins, Bcl-2 and Bcl-X L, leading to apoptosis in gastric epithelial cells. / Matsumoto, Ayako; Isomoto, Hajime; Nakayama, Masaaki; Hisatsune, Junzo; Nishi, Yoshito; Nakashima, Yujiro; Matsushima, Kayoko; Kurazono, Hisao; Nakao, Kazuhiko; Hirayama, Toshiya; Kohno, Shigeru.

In: Digestive Diseases and Sciences, Vol. 56, No. 4, 04.2011, p. 999-1006.

Research output: Contribution to journalArticle

Matsumoto, Ayako ; Isomoto, Hajime ; Nakayama, Masaaki ; Hisatsune, Junzo ; Nishi, Yoshito ; Nakashima, Yujiro ; Matsushima, Kayoko ; Kurazono, Hisao ; Nakao, Kazuhiko ; Hirayama, Toshiya ; Kohno, Shigeru. / Helicobacter pylori VacA reduces the cellular expression of STAT3 and pro-survival Bcl-2 family proteins, Bcl-2 and Bcl-X L, leading to apoptosis in gastric epithelial cells. In: Digestive Diseases and Sciences. 2011 ; Vol. 56, No. 4. pp. 999-1006.
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abstract = "Background: 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 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 L. Aims: This study was conducted to elicit the implication of STAT3 and pro-survival Bcl-2 and Bcl-X L 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-X 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. Results: VacA reduced STAT3, Bcl-2, and Bcl-X L expression in a dose-dependent manner. Knockdown of STAT3, Bcl-2, and Bcl-X 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 L expression. Instead, a c-JUN NH 2-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-X L, in association with JNK activity.",
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T1 - Helicobacter pylori VacA reduces the cellular expression of STAT3 and pro-survival Bcl-2 family proteins, Bcl-2 and Bcl-X L, leading to apoptosis in gastric epithelial cells

AU - Matsumoto, Ayako

AU - Isomoto, Hajime

AU - Nakayama, Masaaki

AU - Hisatsune, Junzo

AU - Nishi, Yoshito

AU - Nakashima, Yujiro

AU - Matsushima, Kayoko

AU - Kurazono, Hisao

AU - Nakao, Kazuhiko

AU - Hirayama, Toshiya

AU - Kohno, Shigeru

PY - 2011/4

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N2 - Background: 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 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 L. Aims: This study was conducted to elicit the implication of STAT3 and pro-survival Bcl-2 and Bcl-X L 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-X 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. Results: VacA reduced STAT3, Bcl-2, and Bcl-X L expression in a dose-dependent manner. Knockdown of STAT3, Bcl-2, and Bcl-X 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 L expression. Instead, a c-JUN NH 2-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-X L, in association with JNK activity.

AB - Background: 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 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 L. Aims: This study was conducted to elicit the implication of STAT3 and pro-survival Bcl-2 and Bcl-X L 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-X 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. Results: VacA reduced STAT3, Bcl-2, and Bcl-X L expression in a dose-dependent manner. Knockdown of STAT3, Bcl-2, and Bcl-X 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 L expression. Instead, a c-JUN NH 2-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-X L, in association with JNK activity.

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KW - B-cell lymphoma (Bcl)-2 and Bcl-X

KW - c-JUN NH -terminal kinase, JNK

KW - Signal transduction and activator of transcription 3, STAT3

KW - Vacuolating cytotoxin, VacA

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