Anacardic acid induces cell apoptosis associated with induction of ATF4-dependent endoplasmic reticulum stress.
Anacardic acid (6-pentadecylsalicylic acid, AA), a natural compound isolated from the traditional medicine Amphipterygium adstringens, has been reported to possess antitumor activities. However, its molecular targets have not been thoroughly studied. Here, we report that AA is a potent inducer of endoplasmic reticulum (ER) stress, leading to apoptosis in hepatoma HepG2 and myeloma U266 cells. Induction of ER stress by AA was supported by a dose- and time-dependent increase in expression of the ER signaling downstream molecules, such as GRP78/BiP, phosphorylated eIF2α, ATF4 and CHOP in both HepG2 and U266 cell lines. Blockage of ATF4 expression by siRNA partially inhibited, while knockdown of CHOP expression by siRNA slightly increased AA-induced cell death in these cells. In addition, AA suppressed HepG2 xenograft tumor growth, associated with increased ER stress in vivo. These results suggest that AA induces tumor cell apoptosis associated with ATF4-dependent ER stress.
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
Hongbiao
H
Huang
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
Xianliang
X
Hua
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China; Guangzhou Research Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, People's Republic of China.
Ningning
N
Liu
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
Xiaofen
X
Li
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
Shouting
S
Liu
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
Xin
X
Chen
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
Chong
C
Zhao
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
Xiaoying
X
Lan
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China.
Changshan
C
Yang
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China; The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, MI 48201-2013, USA.
Q Ping
QP
Dou
State Key Lab of Respiratory Disease, Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical University, Guangdong 510182, People's Republic of China. Electronic address: jliu@gzhmu.edu.cn.
Jinbao
J
Liu
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D048729:Anacardic Acids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000378:metabolism; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
C497109:ATF4 protein, human; D048729:Anacardic Acids; D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; C088115:anacardic acid
ATF4; Anacardic acid; Apoptosis; ER stress