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Amlodipine inhibits Synaptotagmin-4's oncogenic activity on gastric cancer proliferation by targeting calcium signaling.
Huang, Wen; Yang, Shuo; Deng, Minying; Luo, Rongkui; Liang, Huaiyu; Shen, Yanyan; Yang, Biyu; Xu, Chen; Hou, Yingyong.
Afiliação
  • Huang W; Department of Pathology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
  • Yang S; Department of Orthopaedics, People's Hospital of Tongzhou Bay Demonstration Zone, Nantong, Jiangsu, China.
  • Deng M; Department of Orthopaedics, Nantong First People's Hospital, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu, China.
  • Luo R; Department of Pathology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
  • Liang H; Department of Pathology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
  • Shen Y; Department of Pathology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
  • Yang B; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Xu C; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • Hou Y; Department of Pathology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Xuhui District, Shanghai, 200032, China. xuchen1251@yeah.net.
Funct Integr Genomics ; 24(3): 77, 2024 Apr 18.
Article em En | MEDLINE | ID: mdl-38632140
ABSTRACT

BACKGROUND:

Gastric cancer (GC) remains a leading cause of cancer mortality globally. Synaptotagmin-4 (SYT4), a calcium-sensing synaptic vesicle protein, has been implicated in the oncogenesis of diverse malignancies.

PURPOSE:

This study delineates the role of SYT4 in modulating clinical outcomes and biological behaviors in GC.

METHODS:

We evaluated SYT4 expression in GC specimens using bioinformatics analyses and immunohistochemistry. Functional assays included CCK8 proliferation tests, apoptosis assays via flow cytometry, confocal calcium imaging, and xenograft models. Western blotting elucidated MAPK pathway involvement. Additionally, we investigated the impact of the calcium channel blocker amlodipine on cellular dynamics and MAPK pathway activity.

RESULTS:

SYT4 was higher in GC tissues, and the elevated SYT4 was significantly correlated with adverse prognosis. Both univariate and multivariate analyses confirmed SYT4 as an independent prognostic indicator for GC. Functionally, SYT4 promoted tumorigenesis by fostering cellular proliferation, inhibiting apoptosis, and enhancing intracellular Ca2+ influx, predominantly via MAPK pathway activation. Amlodipine pre-treatment attenuated SYT4-driven cell growth and potentiated apoptosis, corroborated by in vivo xenograft assessments. These effects were attributed to MAPK pathway suppression by amlodipine.

CONCLUSION:

SYT4 emerges as a potential prognostic biomarker and a pro-oncogenic mediator in GC through a Ca2+-dependent MAPK mechanism. Amlodipine demonstrates significant antitumor effects against SYT4-driven GC, positing its therapeutic promise. This study underscores the imperative of targeting calcium signaling in GC treatment strategies.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Gástricas / Anlodipino / Sinalização do Cálcio / Sinaptotagminas Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Gástricas / Anlodipino / Sinalização do Cálcio / Sinaptotagminas Idioma: En Ano de publicação: 2024 Tipo de documento: Article