Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL
Open Access
- 21 July 2005
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 42 (3), 588-597
- https://doi.org/10.1002/hep.20807
Abstract
TRAIL exhibits potent anti-tumor activity on systemic administration in mice. Because of its proven in vivo efficacy, TRAIL may serve as a novel anti-neoplastic drug. However, approximately half of the tumor cell lines tested so far are TRAIL resistant, and potential toxic side effects of certain recombinant forms of TRAIL on human hepatocytes have been described. Pretreatment with the proteasome inhibitor MG132 and PS-341 rendered TRAIL-resistant hepatocellular carcinoma (HCC) cell lines but not primary human hepatocytes sensitive for TRAIL-induced apoptosis. We investigated the different levels of possible MG132-induced interference with resistance to apoptotic signal transduction. Although proteasome inhibition efficiently suppressed nuclear factor-kappaB (NF-κB) activity, specific suppression of NF-κB by mutIκBα failed to sensitize TRAIL-resistant cell lines for TRAIL-induced apoptosis. In contrast to the previously reported mechanism of sensitization by 5-fluorouracil (5-FU), cellular FLICE-inhibitory protein (cFLIP)L and cFLIPS were markedly upregulated in the TRAIL death inducing signaling complex (DISC) by proteasome inhibitor pretreatment. Compared with 5-FU pretreatment, caspase-8 was more efficiently recruited to the DISC in MG132 pretreated cells despite the presence of fewer death receptors and more cFLIP in the DISC. But downregulation of cFLIP by short interference RNA (siRNA) further sensitized the HCC cell lines. In conclusion, these results show that otherwise chemotherapy-resistant tumor cells can be sensitized for TRAIL-induced apoptosis at the DISC level in the presence of high levels of cFLIP, which suggests the existence of an additional factor that modulates the interaction of FADD and the TRAIL death receptors. Of clinical relevance, proteasome inhibitors sensitize HCC cells but not primary human hepatocytes for TRAIL-induced apoptosis. (HEPATOLOGY 2005.)Keywords
This publication has 36 references indexed in Scilit:
- Enhanced caspase-8 recruitment to and activation at the DISC is critical for sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by chemotherapeutic drugsCell Death & Differentiation, 2004
- Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8The EMBO Journal, 2002
- c-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosisThe EMBO Journal, 2002
- Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicityNature Medicine, 2001
- Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versionsNature Medicine, 2001
- CD95's deadly mission in the immune systemNature, 2000
- Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligandNature Medicine, 2000
- The CD95 (APO-1/Fas) and the TRAIL (APO-2L) Apoptosis SystemsExperimental Cell Research, 2000
- Safety and antitumor activity of recombinant soluble Apo2 ligandJCI Insight, 1999
- Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivoNature Medicine, 1999