4.6 Article

Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling

Journal

INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 54, Issue 4, Pages 1271-1281

Publisher

SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2019.4704

Keywords

metformin; adenosine monophosphate-activated protein kinase; mammalian target of rapamycin/AKT pathway; apoptosis; human gastric adenocarcinoma AGS cells

Categories

Funding

  1. Hualien Tzu Chi Hospital (Hualien, Taiwan) [TCRD107-55]
  2. [DMR-107-123]

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Metformin is commonly used to treat patients with type 2 diabetes and is associated with a decreased risk of cancer. Previous studies have demonstrated that metformin can act alone or in synergy with certain anticancer agents to achieve anti-neoplastic effects on various types of tumors via adenosine monophosphate-activated protein kinase (AMPK) signaling. However, the role of metformin in AMPK-mediated apoptosis of human gastric cancer cells is poorly understood. In the current study, metformin exhibited a potent anti-proliferative effect and induced apoptotic characteristics in human AGS gastric adenocarcinoma cells, as demonstrated by MTT assay, morphological observation method, terminal deoxynucleotidyl transferase dUTP nick end labeling and caspase-3/7 assay kits. Western blot analysis demonstrated that treatment with metformin increased the phosphorylation of AMPK, and decreased the phosphorylation of AKT, mTOR and p70S6k. Compound C (an AMPK inhibitor) suppressed AMPK phosphorylation and significantly abrogated the effects of metformin on AGS cell viability. Metformin also reduced the phosphorylation of mitogen-activated protein kinases (ERK, JNK and p38). Additionally, metformin significantly increased the cellular ROS level and included loss of mitochondrial membrane potential (Delta psi m). Metformin altered apoptosis-associated signaling to downregulate the BAD phosphorylation and Bcl-2, pro-caspase-9, pro-caspase-3 and pro-caspase-7 expression, and to upregulate BAD, cytochrome c, and Apaf-1 proteins levels in AGS cells. Furthermore, z-VAD-fmk (a pan-caspase inhibitor) was used to assess mitochondria-mediated caspase-dependent apoptosis in metformin-treated AGS cells. The findings demonstrated that metformin induced AMPK-mediated apoptosis, making it appealing for development as a novel anticancer drug for the treating gastric cancer.

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