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Int. J. Mol. Sci. 2015, 16(9), 22676-22691; doi:10.3390/ijms160922676

Poncirin Induces Apoptosis in AGS Human Gastric Cancer Cells through Extrinsic Apoptotic Pathway by up-Regulation of Fas Ligand

1
Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Gazwa, Jinju 660-701, Korea
2
Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Korea
3
Gyeongnam Department of Environment Toxicology and Chemistry, Toxicity Screening Research Center, Korea Institute of Toxicology, Jinju 666-844, Korea
4
Department of Nursing Science, International University of Korea, Jinju 660-759, Korea
*
Author to whom correspondence should be addressed.
Academic Editor: Maurizio Battino
Received: 9 June 2015 / Revised: 10 September 2015 / Accepted: 11 September 2015 / Published: 18 September 2015
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Abstract

Poncirin, a natural bitter flavanone glycoside abundantly present in many species of citrus fruits, has various biological benefits such as anti-oxidant, anti-microbial, anti-inflammatory and anti-cancer activities. The anti-cancer mechanism of Poncirin remains elusive to date. In this study, we investigated the anti-cancer effects of Poncirin in AGS human gastric cancer cells (gastric adenocarcinoma). The results revealed that Poncirin could inhibit the proliferation of AGS cells in a dose-dependent manner. It was observed Poncirin induced accumulation of sub-G1 DNA content, apoptotic cell population, apoptotic bodies, chromatin condensation, and DNA fragmentation in a dose-dependent manner in AGS cells. The expression of Fas Ligand (FasL) protein was up-regulated dose dependently in Poncirin-treated AGS cells Moreover, Poncirin in AGS cells induced activation of Caspase-8 and -3, and subsequent cleavage of poly(ADP-ribose) polymerase (PARP). Inhibitor studies’ results confirm that the induction of caspase-dependent apoptotic cell death in Poncirin-treated AGS cells was led by the Fas death receptor. Interestingly, Poncirin did not show any effect on mitochondrial membrane potential (ΔΨm), pro-apoptotic proteins (Bax and Bak) and anti-apoptotic protein (Bcl-xL) in AGS-treated cells followed by no activation in the mitochondrial apoptotic protein caspase-9. This result suggests that the mitochondrial-mediated pathway is not involved in Poncirin-induced cell death in gastric cancer. These findings suggest that Poncirin has a potential anti-cancer effect via extrinsic pathway-mediated apoptosis, possibly making it a strong therapeutic agent for human gastric cancer. View Full-Text
Keywords: Poncirin; gastric adenocarcinoma; AGS cells; FasL; caspases; apoptosis Poncirin; gastric adenocarcinoma; AGS cells; FasL; caspases; apoptosis
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MDPI and ACS Style

Saralamma, V.V.G.; Nagappan, A.; Hong, G.E.; Lee, H.J.; Yumnam, S.; Raha, S.; Heo, J.D.; Lee, S.J.; Lee, W.S.; Kim, E.H.; Kim, G.S. Poncirin Induces Apoptosis in AGS Human Gastric Cancer Cells through Extrinsic Apoptotic Pathway by up-Regulation of Fas Ligand. Int. J. Mol. Sci. 2015, 16, 22676-22691.

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