IMR Press / FBE / Volume 4 / Issue 6 / DOI: 10.2741/e536

Frontiers in Bioscience-Elite (FBE) is published by IMR Press from Volume 13 Issue 2 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article

Proteasome inhibition overcomes TRAIL resistance in human hepatoblastoma cells

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1 Department of Pediatric Surgery, University Children’s Hospital Tubingen, Hoppe-Seyler-Str. 3, 72076 Tubingen, Germany
2 Institute of Pathology, Hospital Leonberg, 71229 Leonberg, Germany

Academic Editor: Steven Warmann

Front. Biosci. (Elite Ed) 2012, 4(6), 2194–2202; https://doi.org/10.2741/e536
Published: 1 January 2012
(This article belongs to the Special Issue Hepatoblastoma)
Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is responsible for cell death in many cancer cells while being non-toxic for most normal cells. In this study, we investigated the role of TRAIL in human hepatoblastoma (HB) cells and analyzed different approaches to reverse TRAIL resistance in these tumors. Death receptors DR4 and DR5 expression was found on all analyzed primary HB samples and on the cell lines HuH6 and HepT1 by immunofluorescence staining. Recombinant TRAIL alone did not induce in vitro cytotoxicity. Decoy receptor blocking by antibodies led to moderate effects in HepT1 but not in HUH6 cells, whereas FLIP knock-down using siRNA rendered HUH6 cells but not HepT1 cells sensible to TRAIL. Bcl-2 inhibition with ABT-737 enhanced TRAIL-mediated apoptosis in all HB cells. Strongest cytotoxic TRAIL effects were seen in HB cell lines with synchronous proteasome inhibition using bortezomib. FLIP and Bcl-2 contributed to the TRAIL resistance in HB. Overcoming TRAIL resistance in HB by proteasome inhibitors has been identified a possible additive to improve treatment results in HB patients with drug resistant tumors.

Keywords
Hepatoblastoma
TRAIL
TRAIL resistance
Proteasome inhibitors
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