6533b837fe1ef96bd12a2891

RESEARCH PRODUCT

The histone deacetylase inhibitor suberoylanilide hydroxamic acid sensitizes human hepatocellular carcinoma cells to TRAIL-induced apoptosis by TRAIL-DISC activation

Daniela CarlisiMarianna LauricellaSonia EmanueleRenza VentoAndrea SantulliPietro Di FazioAntonella D’anneoGiovanni TesoriereLiliana Angileri

subject

Death Domain Receptor Signaling Adaptor ProteinsCancer Researchmedicine.medical_specialtyProgrammed cell deathCarcinoma Hepatocellularmedicine.drug_classmedicine.medical_treatmentBlotting WesternCASP8 and FADD-Like Apoptosis Regulating ProteinDown-RegulationAntineoplastic AgentsApoptosisBiologyHydroxamic AcidsHDACI TRAIL apoptosisInternal medicineSettore BIO/10 - BiochimicamedicineHumansProtein kinase BVorinostatLiver NeoplasmsHistone deacetylase inhibitorNF-kappa Bmedicine.diseaseReceptors TNF-Related Apoptosis-Inducing LigandCytokineEndocrinologyOncologyDrug Resistance NeoplasmApoptosisHepatocellular carcinomaCancer researchTumor necrosis factor alphaSignal transductionProto-Oncogene Proteins c-akt

description

Abstract This paper shows that the histone deacetylase inhibitor SAHA sensitised at sub-toxic doses human hepatocellular carcinoma cells (HepG2, Hep3B and SK-Hep1) to TRAIL-induced apoptosis, while it was ineffective in primary human hepatocytes (PHHs). In particular in HCC cells SAHA increased the expression of death receptor 5 (DR5) and caused a decrement of c-Flip. These two modifications provoked in the presence of TRAIL the rapid production of TRAIL-DISC and the activation of caspase-8. Consequently SAHA/TRAIL combination induced many apoptotic events, such as a cleavage of Bid into tBid, dissipation of mitochondrial membrane potential, activation of caspase-3 with the consequent cleavage of both NF-kB and Akt. The decrease in NF-kB level seemed to be responsible for the reduction in the content of IAP family antiapoptotic proteins while the decrease in Akt level caused a reduction in phospho-Bad. These events led to the activation of caspase-9, which contributed to the strong apoptotic activity of TRAIL. Sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by SAHA may suggest new strategies for the treatment of liver tumours.

yearjournalcountryeditionlanguage
2009-04-07
10.1016/j.ejca.2009.06.024http://hdl.handle.net/10447/47857