title: Parthenolide sensitizes hepatocellular carcinoma cells to TRAIL by inducing the expression of death receptors through inhibition of STAT3 activation.
abstract: This article shows that HepG2, Hep3B, and SK-Hep1 cells, three lines of human hepatocellular carcinoma (HCC) cells, are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Parthenolide, a sesquiterpene lactone found in European feverfew, has been shown to exert both anti-inflammatory and anti-cancer activities. This article demonstrates that co-treatment with parthenolide and TRAIL-induced apoptosis with synergistic interactions in the three lines of HCC cells. In order to explain these effects we ascertained that parthenolide increased either at protein or mRNA level the total content of death receptors TRAIL-R1 and -R2 as well as their surface expression. These effects were found in the three cell lines in the case of TRAIL-R2, while for TRAIL-R1 they were observed in HepG2 and SK-Hep1 cells, but not in Hep3B cells. We suggest that the effects of parthenolide on death receptors depend on the decrease in the level of phosphorylated and active forms of STAT proteins, an event which could be a consequence of the inhibitory effect exerted by parthenolide on the activation of JAK proteins. In agreement with this hypothesis treatment with STAT3 siRNA increased in HCC cells the effect of parthenolide on the expression of death receptors. Sensitization by parthenolide to TRAIL stimulated in the three cell lines the extrinsic mechanism of apoptosis with the activation of both caspases 8 and 3, whereas mitochondria were not involved in the process. Our results suggest that co-treatment with parthenolide and TRAIL could represent a new important therapeutic strategy for hepatic tumors.
authors.affiliation: Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche, Sezione di Scienze Biochimiche, Università di Palermo, Policlinico, Palermo, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Carlisi
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Anneo
authors.forename: Liliana
authors.initials: L
authors.lastname: Angileri
authors.forename: Marianna
authors.initials: M
authors.lastname: Lauricella
authors.forename: Sonia
authors.initials: S
authors.lastname: Emanuele
authors.forename: Andrea
authors.initials: A
authors.lastname: Santulli
authors.forename: Renza
authors.initials: R
authors.lastname: Vento
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tesoriere
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D053218:Receptors, Death Domain / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D053218:Receptors, Death Domain; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; C002669:parthenolide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D053612:Janus Kinases; D020169:Caspases