%0 Journal Article
%T TRAIL-induced apoptosis of hepatocellular carcinoma cells is augmented by targeted therapies
%A Bruno Christian Koehler
%A Toni Urbanik
%A Binje Vick
%A Regina Johanna Boger
%A Steffen Heeger
%A Peter R Galle
%A Marcus Schuchmann
%A Henning Schulze-Bergkamen
%J World Journal of Gastroenterology
%D 2009
%I Baishideng Publishing Group Co. Limited
%X AIM: To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors, in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL), on overcoming TRAIL resistance in hepatocellular carcinoma (HCC) and to study the efficacy of agonistic TRAIL antibodies, as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis.METHODS: Surface expression of TRAIL receptors (TRAIL-R1-4) and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting, respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs. HCC cells were treated with kinase inhibitors and chemotherapeutic drugs. Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.RESULTS: TRAIL-R1 and -R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However, treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates. Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002 [inhibition of phosphoinositol-3-kinase (PI3K)], AG1478 (epidermal growth factor receptor kinase), PD98059 (MEK1), rapamycin (mammalian target of rapamycin) and the multi-kinase inhibitor Sorafenib. Furthermore, the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance: knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells. Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION: Our data identify the blockage of survival kinases, combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.
%K Hepatocellular carcinoma
%K Apoptosis
%K Tumor necrosis factor-related apoptosis inducing ligand
%K BCL-xL
%K MCL-1
%K 5-fluorouracil
%K Doxorubicin
%K Sorafenib
%K Phosphoinositol-3-kinase
%K (Mitogen-activated protein kinase)/(extracellular signal regulated kinase) kinase
%K c-Jun N-terminal kinase
%U http://www.wjgnet.com/1007-9327/full/v15/i47/5924.htm