title: 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.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Gazwa, Jinju 660-701, Korea. gowdavenu27@gmail.com.
authors.forename: Venu Venkatarame Gowda
authors.initials: VV
authors.lastname: Saralamma
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Korea. arulbiotechtnau@gmail.com.
authors.forename: Arulkumar
authors.initials: A
authors.lastname: Nagappan
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Gazwa, Jinju 660-701, Korea. hge@gnu.ac.kr.
authors.forename: Gyeong Eun
authors.initials: GE
authors.lastname: Hong
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Gazwa, Jinju 660-701, Korea. rock05072000@naver.com.
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Gazwa, Jinju 660-701, Korea. silviayumnam@gmail.com.
authors.forename: Silvia
authors.initials: S
authors.lastname: Yumnam
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Gazwa, Jinju 660-701, Korea. suchibiodash@gmail.com.
authors.forename: Suchismita
authors.initials: S
authors.lastname: Raha
authors.affiliation: Gyeongnam Department of Environment Toxicology and Chemistry, Toxicity Screening Research Center, Korea Institute of Toxicology, Jinju 666-844, Korea. jdher@kitox.re.kr.
authors.forename: Jeong Doo
authors.initials: JD
authors.lastname: Heo
authors.affiliation: Gyeongnam Department of Environment Toxicology and Chemistry, Toxicity Screening Research Center, Korea Institute of Toxicology, Jinju 666-844, Korea. sjlee@kitox.re.kr.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-702, Korea. lwshmo@gnu.ac.kr.
authors.forename: Won Sup
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Department of Nursing Science, International University of Korea, Jinju 660-759, Korea. iuknurse@nate.com.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Gazwa, Jinju 660-701, Korea. gonskim@gnu.ac.kr.
authors.forename: Gon Sup
authors.initials: GS
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002957:Citrus / Q000737:chemistry; D053938:DNA Fragmentation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D013270:Stomach / Q000187:drug effects* / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005419:Flavonoids; C119641:poncirin; D020169:Caspases
keywords: AGS cells; FasL; Poncirin; apoptosis; caspases; gastric adenocarcinoma