TRAIL-induced Apoptosis of Hepatocellular Carcinoma Cells is Augmented by Targeted Therapies

Overview

Journal World J Gastroenterol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2009 Dec 17

PMID 20014456

Citations 13

Authors

Bruno-Christian Koehler

Toni Urbanik

Binje Vick

Regina-Johanna Boger

Steffen Heeger

Peter-R Galle

Marcus Schuchmann

Henning Schulze-Bergkamen

Affiliations

Soon will be listed here.

Abstract

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-x(L) were analyzed by flow cytometry and Western blotting, respectively. Knock-down of MCL-1 and BCL-x(L) 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-x(L) 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-x(L) 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.

Citing Articles

Potentiation of TRAIL‑induced cell death by nonsteroidal anti‑inflammatory drug in human hepatocellular carcinoma cells through the ER stress‑dependent autophagy pathway.

Lee S, Moon H, Lee Y, Kang C, Kim S Oncol Rep. 2020; 44(3):1136-1148.

PMID: 32705218 PMC: 7388578. DOI: 10.3892/or.2020.7662.

Cancer vaccines and immunotherapeutic approaches in hepatobiliary and pancreatic cancers.

Hochnadel I, Kossatz-Boehlert U, Jedicke N, Lenzen H, Manns M, Yevsa T Hum Vaccin Immunother. 2017; 13(12):2931-2952.

PMID: 29112462 PMC: 5718787. DOI: 10.1080/21645515.2017.1359362.

Overexpression of c-Jun contributes to sorafenib resistance in human hepatoma cell lines.

Haga Y, Kanda T, Nakamura M, Nakamoto S, Sasaki R, Takahashi K PLoS One. 2017; 12(3):e0174153.

PMID: 28323861 PMC: 5360329. DOI: 10.1371/journal.pone.0174153.

HBV polymerase overexpression due to large core gene deletion enhances hepatoma cell growth by binding inhibition of microRNA-100.

Huang Y, Tseng Y, Lin W, Hung G, Chen T, Wang T Oncotarget. 2016; 7(8):9448-61.

PMID: 26824500 PMC: 4891051. DOI: 10.18632/oncotarget.7021.

Pan-Bcl-2 inhibitor Obatoclax is a potent late stage autophagy inhibitor in colorectal cancer cells independent of canonical autophagy signaling.

Koehler B, Jassowicz A, Scherr A, Lorenz S, Radhakrishnan P, Kautz N BMC Cancer. 2015; 15:919.

PMID: 26585594 PMC: 4653869. DOI: 10.1186/s12885-015-1929-y.

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