7). Finally, our results show the importance of the Mdm2-NEDD8 network in Selleck PD0325901 HuR overexpression during malignant transformation, supporting the role of HuR in tumorigenesis. The potential of antitumor activity for the NEDD8-activating enzyme inhibitor, MLN4924, has been shown in human colon and lung tumor xenograft models in immunocompromised mice.34 Taken together, HuR is a new target for NEDDylation, and NEDD-dependent regulation plays a crucial role as a principal conductor of a new regulatory mechanism. Our findings might represent a useful tool to uncover new therapeutic strategies for HCC and

colon cancer. In closing, our results show that NEDDylation is a novel mechanism for HuR regulation, which broadly reveals its influence on the cellular post-transcriptional regulatory machinery. The authors particularly acknowledge the patients enrolled in this study for their participation

and the Basque Biobank for Research-OEHUN for its collaboration in providing the human samples and the clinical information used in this project with appropriate ethics approval. The authors are grateful to Dr. Juan Burgos Selleck CX-4945 for selection of the human samples and Dr. Félix Royo for helping with statistical analysis. Additional Supporting Information may be found in the online version of this article. “
“As the result of an increasing incidence and a prevalent therapy resistance medchemexpress of hepatocellular carcinoma (HCC), there is a strong need for novel strategies to enhance treatment responses in HCC. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has been proposed as a promising anticancer drug because it can selectively induce apoptosis in cancer cells, but not in healthy cells. Nevertheless, most tumor cells show TRAIL resistance, emphasizing the requirement for apoptosis-sensitizing agents and TRAIL molecules with improved tumor specificity. In this study, we employed a recombinant TRAIL molecule, in which three TRAIL protomers were expressed as a single polypeptide chain (scTRAIL), and a novel TRAIL variant, in which scTRAIL was additionally fused to an antibody fragment recognizing epidermal growth

factor receptor (EGFR) to improve its HCC-targeting properties. We analyzed the proapoptotic effects of both TRAIL versions in combination with the proteasome inhibitor bortezomib (BZB) in hepatoma cells and primary human hepatocytes as well as in intact explants from HCC and healthy liver tissue. We demonstrate that EGFR-targeted TRAIL in combination with BZB induced significantly higher caspase activation and cell death in hepatoma cells, but not in primary hepatocytes. Importantly, when incubated with fresh liver explants, the combination of EGFR-targeted TRAIL and BZB displayed selective cytotoxicity for HCC, but not for tumor-free liver tissue, which could even be verified in liver explants from the same individuals.