title: TRAIL enhances apoptosis of human hepatocellular carcinoma cells sensitized by hepatitis C virus infection: therapeutic implications.
abstract: Hepatitis C virus (HCV) infection causes chronic liver diseases leading to hepatocellular carcinoma (HCC) and liver failure. We have previously shown that HCV sensitizes hepatocytes to mitochondrial apoptosis via the TRAIL death receptors DR4 and DR5. Although TRAIL and its receptors are selective targets for cancer therapy, their potential against HCC with chronic HCV infection has not been explored yet. Here we show that HCV induces DR4/DR5-dependent activation of caspase-8 leading to elevation of apoptotic signaling in infected cells and also present TRAIL effect in HCV-induced apoptotic signaling. HCV induced proteolytic cleavage of caspase-9 by stimulating DR4 and DR5, resulting in subsequent cleavage of caspase-3. Further, HCV-induced proteolytic cleavage in caspase-8, caspase-9, and caspase-3 was enhanced in the presence of recombinant TRAIL. HCV-induced cleavage in caspase-9 and increase in caspase-3/7 activity was completely suppressed by silencing of either DR4 or DR5. Perturbing DR4/DR5-caspase-8 signaling complex by silencing DR4 and DR5 or by chemical inhibitor specific to caspase-8 led to decrease of HCV-induced cleavage of poly(ADP-ribose) polymerase (PARP), a substrate for caspase-3 during apoptosis, indicating the functional role of caspase-8 in HCV-induced apoptotic signaling network. Furthermore, TRAIL enhanced PARP cleavage in apoptotic response induced by HCV infection, indicating the effect of TRAIL for the induction of selective apoptosis of HCC cells infected with HCV. Given the importance of apoptosis in HCC development, our data suggest that HCV-induced DR4 and DR5 may be considered as an attractive target for TRAIL therapy against HCC with chronic HCV infection.
authors.affiliation: Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, South Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Jang
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Seong-Jun
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, South Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Cho
authors.affiliation: Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, South Korea.
authors.forename: Soung Won
authors.initials: SW
authors.lastname: Jeong
authors.affiliation: Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, South Korea.
authors.forename: Eui Ju
authors.initials: EJ
authors.lastname: Park
authors.affiliation: Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, South Korea.
authors.forename: Woong Cheul
authors.initials: WC
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea.
authors.forename: Sae Hwan
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, College of Medicine, Soonchunhyang University, Bucheon, South Korea.
authors.forename: Sang Gyune
authors.initials: SG
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, Soonchunhyang University, Bucheon, South Korea.
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, College of Medicine, Soonchunhyang University, Cheonan, South Korea.
authors.forename: Hong Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul, South Korea.
authors.forename: Boo Sung
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Lin
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8