Caffeic acid phenethyl ester enhances TRAIL-mediated apoptosis via CHOP-induced death receptor 5 upregulation in hepatocarcinoma Hep3B cells.
Caffeic acid phenethyl ester (CAPE) exhibits various pharmaceutical properties, including anti-bacterial, anti-inflammatory, anti-viral, anti-cancer, and anti-oxidative activity. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been a promising anti-cancer agent that preferentially induces cancer cell apoptosis with negligible cytotoxicity toward normal cells. Therefore, the present study investigated whether CAPE promotes TRAIL-mediated cytotoxicity in hepatocarcinoma Hep3B cells. The present study demonstrated that CAPE sensitized TRAIL-mediated cell death in Hep3B carcinoma cells. The percentages of the apoptotic cells and annexin-V(+) cells significantly increased in combined treatment with CAPE and TRAIL (CAPE/TRAIL). Treatment with pancaspase inhibitor, z-VAD-fmk, attenuated CAPE/TRAIL-induced apoptosis, suggesting that the combined treatment triggers caspase-dependent apoptosis. Additionally, we found that CAPE stimulated the expression of death receptor 5 (DR5) and treatment with DR5/Fc chimera protein significantly blocked CAPE/TRAIL-induced apoptosis, which indicates that CAPE/TRAIL stimulated apoptosis through the binding of TRAIL to DR5. Moreover, expression of transcription factor C/EBP homologous protein (CHOP) markedly increased in response to CAPE and transient knockdown of CHOP abolished CAPE/TRAIL-mediated apoptosis. These results suggest that CHOP is a key regulator in CAPE/TRAIL-mediated apoptosis. Taken together, the present study found that CAPE significantly enhanced TRAIL-mediated apoptosis in Hep3B carcinoma cells and suggested that CAPE has promising potential in chemoprevention of hepatocellular carcinomas.
Department of Marine Life Sciences, Jeju National University, Jeju, 63243, Republic of Korea.
Matharage Gayani
MG
Dilshara
Department of Marine Life Sciences, Jeju National University, Jeju, 63243, Republic of Korea.
Rajapaksha Gedara Prasad Tharanga
RG
Jayasooriya
Department of Marine Life Sciences, Jeju National University, Jeju, 63243, Republic of Korea.
Sang Rul
SR
Park
Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan, 47340, Republic of Korea.
Yung-Hyun
YH
Choi
Department of Microbiology, College of Medicine, Inje University, Busan, 47392, Republic of Korea.
Il-Whan
IW
Choi
Department of Marine Life Sciences, Jeju National University, Jeju, 63243, Republic of Korea. immunkim@jejunu.ac.kr.
Gi-Young
GY
Kim
D017209:Apoptosis / Q000187:drug effects*; D002109:Caffeic Acids / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis*; D051742:Transcription Factor CHOP / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
D002109:Caffeic Acids; C497249:DDIT3 protein, human; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D051742:Transcription Factor CHOP; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
C/EBP homologous protein; Caffeic acid phenethyl ester; Death receptor 5; Tumor necrosis factor-related apoptosis-inducing ligand