Proteasome Inhibition Sensitizes Hepatocellular Carcinoma Cells, But Not Human Hepatocytes, to TRAIL *

• DOI: 10.1002/hep.20807
• Publication Date: 2005-07-21T18:46:44Z
• Authors: Tom M. Ganten; Ronald Koschny; Tobias L. Haas; Jaromir Sykora; Min Li-Weber; Kerstin Herzer; Henning Walczak
• Keywords: MG132

Abstract TRAIL exhibits potent anti-tumor activity on systemic administration in mice. Because of its proven vivo efficacy, may serve as a novel anti-neoplastic drug. However, approximately half the tumor cell lines tested so far are resistant, and potential toxic side effects certain recombinant forms human hepatocytes have been described. Pretreatment with proteasome inhibitor MG132 PS-341 rendered TRAIL-resistant hepatocellular carcinoma (HCC) but not primary sensitive for TRAIL-induced apoptosis. We investigated different levels possible MG132-induced interference resistance to apoptotic signal transduction. Although inhibition efficiently suppressed nuclear factor-kappaB (NF-κB) activity, specific suppression NF-κB by mutIκBα failed sensitize In contrast previously reported mechanism sensitization 5-fluorouracil (5-FU), cellular FLICE-inhibitory protein (cFLIP)L cFLIPS were markedly upregulated death inducing signaling complex (DISC) pretreatment. Compared 5-FU pretreatment, caspase-8 was more recruited DISC pretreated cells despite presence fewer receptors cFLIP DISC. But downregulation short RNA (siRNA) further sensitized HCC lines. conclusion , these results show that otherwise chemotherapy-resistant can be apoptosis at level high cFLIP, which suggests existence an additional factor modulates interaction FADD receptors. Of clinical relevance, inhibitors (Hepatology 2005.)