Terminalia Chebula provides protection against dual modes of necroptotic and apoptotic cell death upon death receptor ligation.
Death receptor (DR) ligation elicits two different modes of cell death (necroptosis and apoptosis) depending on the cellular context. By screening a plant extract library from cells undergoing necroptosis or apoptosis, we identified a water extract of Terminalia chebula (WETC) as a novel and potent dual inhibitor of DR-mediated cell death. Investigation of the underlying mechanisms of its anti-necroptotic and anti-apoptotic action revealed that WETC or its constituents (e.g., gallic acid) protected against tumor necrosis factor-induced necroptosis via the suppression of TNF-induced ROS without affecting the upstream signaling events. Surprisingly, WETC also provided protection against DR-mediated apoptosis by inhibition of the caspase cascade. Furthermore, it activated the autophagy pathway via suppression of mTOR. Of the WETC constituents, punicalagin and geraniin appeared to possess the most potent anti-apoptotic and autophagy activation effect. Importantly, blockage of autophagy with pharmacological inhibitors or genetic silencing of Atg5 selectively abolished the anti-apoptotic function of WETC. These results suggest that WETC protects against dual modes of cell death upon DR ligation. Therefore, WETC might serve as a potential treatment for diseases characterized by aberrantly sensitized apoptotic or non-apoptotic signaling cascades.
Department of Pharmacology, Research Institute for Medical Science, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
Yoonjung
Y
Lee
Department of Pharmacology, Research Institute for Medical Science, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
Hee Sun
HS
Byun
Department of Pharmacology, Research Institute for Medical Science, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
Jeong Ho
JH
Seok
Department of Pharmacology, Research Institute for Medical Science, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
Kyeong Ah
KA
Park
Department of Pharmacology, Research Institute for Medical Science, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
Minho
M
Won
Department of Pharmacology, Research Institute for Medical Science, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
Wonhyoung
W
Seo
Department of Pharmacology, Research Institute for Medical Science, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
So-Ra
SR
Lee
Department of Pharmacology, Research Institute for Medical Science, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
Kidong
K
Kang
Department of Dermatology, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
Kyung-Cheol
KC
Sohn
Eco-Friendly New Materials Reserch Center, Korea Research Institute of Chemical Technology, 141 Daejeon 34114, Republic of Korea.
Ill Young
IY
Lee
Liver &Immunology Research Center, Oriental Hospital of Daejeon University, Daejeon 302-122, Republic of Korea.
Hyeong-Geug
HG
Kim
Liver &Immunology Research Center, Oriental Hospital of Daejeon University, Daejeon 302-122, Republic of Korea.
Chang Gue
CG
Son
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Han-Ming
HM
Shen
Department of Pharmacology, Research Institute for Medical Science, College of Medicine, Chungnam National University, Daejeon 301-131, Republic of Korea.
Gang Min
GM
Hur
D016923:Cell Death / Q000187:drug effects*; D005960:Glucosides / Q000302:isolation & purification / Q000378:metabolism; D047348:Hydrolyzable Tannins / Q000302:isolation & purification / Q000378:metabolism; D010936:Plant Extracts / Q000302:isolation & purification / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism*; D029766:Terminalia / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D005960:Glucosides; D047348:Hydrolyzable Tannins; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D053218:Receptors, Death Domain; D014409:Tumor Necrosis Factor-alpha; C024603:Geraniin; C115642:punicalagin