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

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.

• Authors: Venu Venkatarame Gowda Saralamma, Arulkumar Nagappan, Gyeong Eun Hong, Ho Jeong Lee, Silvia Yumnam, Suchismita Raha, Jeong Doo Heo, Sang Joon Lee, Won Sup Lee, Eun Hee Kim, Gon Sup Kim
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 16 Issue 9 Pg. 22676-91 (Sep 18 2015) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 26393583 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• FASLG protein, human
• Fas Ligand Protein
• Flavonoids
• poncirin
• Caspases

Topics

• Adenocarcinoma (drug therapy, genetics, metabolism, pathology)
• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Line, Tumor
• Citrus (chemistry)
• DNA Fragmentation (drug effects)
• Fas Ligand Protein (genetics, metabolism)
• Flavonoids (chemistry, pharmacology)
• Gastric Mucosa (metabolism)
• Humans
• Signal Transduction (drug effects)
• Stomach (drug effects, pathology)
• Stomach Neoplasms (drug therapy, genetics, metabolism, pathology)
• Up-Regulation (drug effects)