title: Sorafenib enhances proteasome inhibitor-mediated cytotoxicity via inhibition of unfolded protein response and keratin phosphorylation.
abstract: Hepatocellular carcinoma (HCC) is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Recent studies of the molecular mechanisms responsible for tumor initiation and progression have identified several potential molecular targets in HCC. Sorafenib is a multi-kinase inhibitor shown to have survival benefits in advanced HCC. It acts by inhibiting the serine/threonine kinases and the receptor type tyrosine kinases. In preclinical experiments sorafenib had anti-proliferative activity in hepatoma cells and it reduced tumor angiogenesis and increased apoptosis. Here, we demonstrate for the first time that the cytotoxic mechanisms of sorafenib include its inhibitory effects on protein ubiquitination, unfolded protein response (UPR) and keratin phosphorylation in response to endoplasmic reticulum (ER) stress. Moreover, we show that combined treatment with sorafenib and proteasome inhibitors (PIs) synergistically induced a marked increase in cell death in hepatoma- and hepatocyte-derived cells. These observations may open the way to potentially interesting treatment combinations that may augment the effect of sorafenib, possibly including drugs that promote ER stress. Because sorafenib blocked the cellular defense mechanisms against hepatotoxic injury not only in hepatoma cells but also in hepatocyte-derived cells, we must be careful to avoid severe liver injury.
authors.affiliation: Third Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Honma
authors.forename: Masaru
authors.initials: M
authors.lastname: Harada
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death; D045744:Cell Line, Tumor; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007633:Keratins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D061988:Proteasome Inhibitors / Q000633:toxicity*; D000077157:Sorafenib; D054875:Ubiquitination / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D061988:Proteasome Inhibitors; D009536:Niacinamide; D007633:Keratins; D000077157:Sorafenib
keywords: 4', 6-diamidino-2-phenylindole; ALLN; ATF; Ab; Apoptosis; Autophagy; C/EBP homologous protein; CHOP; DAPI; ER; Endoplasmic reticulum stress; GADD153; GFP; HCC; Hepatocellular carcinoma; IRE; JNK; K; LC3; MA; MAPK; MDB; Mallory–Denk body; Necrosis; PARP; PDGFR; PERK; PI; PKR-like ER kinase; TRAF2; UPR; VEGFR; X-box binding protein 1; XBP1; acetyl-leucyl-leucyl-norleucinal; activating transcription factor; antibody; c-Jun N-terminal kinase; eIF2; endoplasmic reticulum; eukaryotic translation-initiation factor 2; green fluorescent protein; growth arrest DNA damage 153; hepatocellular carcinoma; inositol-requiring protein; keratin; light chain 3; mTOR; mammalian target of rapamycin; methyladenine; mitogen-activated protein kinase; platelet-derived growth factor receptor; poly-ADP-ribose-polymerase; proteasome inhibitor; tumor necrosis factor receptor-associated factor-2; unfolded protein response; vascular endothelial growth factor receptor