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

  • Authors:
    • Chi-Cheng Lu
    • Jo-Hua Chiang
    • Fuu-Jen Tsai
    • Yuan-Man Hsu
    • Yu-Ning Juan
    • Jai-Sing Yang
    • Hong-Yi Chiu
  • View Affiliations / Copyright

    Affiliations: Department of Sport Performance, National Taiwan University of Sport, Taichung 40404, Taiwan, R.O.C., Department of Nursing, Chung Jen Catholic Junior College, Chiayi 62241, Taiwan, R.O.C., Human Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan, R.O.C., Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan, R.O.C., Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40447, Taiwan, R.O.C., Department of Pharmacy, Buddhist Tzu Chi General Hospital, Hualien 97002, Taiwan, R.O.C.
    Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1271-1281
    |
    Published online on: January 30, 2019
       https://doi.org/10.3892/ijo.2019.4704
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Abstract

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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Copy and paste a formatted citation
Spandidos Publications style
Lu C, Chiang J, Tsai F, Hsu Y, Juan Y, Yang J and Chiu H: Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling. Int J Oncol 54: 1271-1281, 2019.
APA
Lu, C., Chiang, J., Tsai, F., Hsu, Y., Juan, Y., Yang, J., & Chiu, H. (2019). Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling. International Journal of Oncology, 54, 1271-1281. https://doi.org/10.3892/ijo.2019.4704
MLA
Lu, C., Chiang, J., Tsai, F., Hsu, Y., Juan, Y., Yang, J., Chiu, H."Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling". International Journal of Oncology 54.4 (2019): 1271-1281.
Chicago
Lu, C., Chiang, J., Tsai, F., Hsu, Y., Juan, Y., Yang, J., Chiu, H."Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling". International Journal of Oncology 54, no. 4 (2019): 1271-1281. https://doi.org/10.3892/ijo.2019.4704
Copy and paste a formatted citation
x
Spandidos Publications style
Lu C, Chiang J, Tsai F, Hsu Y, Juan Y, Yang J and Chiu H: Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling. Int J Oncol 54: 1271-1281, 2019.
APA
Lu, C., Chiang, J., Tsai, F., Hsu, Y., Juan, Y., Yang, J., & Chiu, H. (2019). Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling. International Journal of Oncology, 54, 1271-1281. https://doi.org/10.3892/ijo.2019.4704
MLA
Lu, C., Chiang, J., Tsai, F., Hsu, Y., Juan, Y., Yang, J., Chiu, H."Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling". International Journal of Oncology 54.4 (2019): 1271-1281.
Chicago
Lu, C., Chiang, J., Tsai, F., Hsu, Y., Juan, Y., Yang, J., Chiu, H."Metformin triggers the intrinsic apoptotic response in human AGS gastric adenocarcinoma cells by activating AMPK and suppressing mTOR/AKT signaling". International Journal of Oncology 54, no. 4 (2019): 1271-1281. https://doi.org/10.3892/ijo.2019.4704
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