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Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling.
International Journal of Oncology 2019 January 31
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 (ΔΨm). 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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