Article

A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways.

Cell Death & Disease (Impact Factor: 5.18). 02/2014; 5:e1079. DOI: 10.1038/cddis.2014.54
Source: PubMed

ABSTRACT Neuroblastoma (NB) is the most common extracranial neoplasm in children. In NB, loss of p53 function is largely due to cytoplasmic sequestration rather than mutation. Ubiquitin-conjugating enzyme E2 N (UBE2N), also known as Ubc13, is an E2 ubiquitin-conjugating enzyme that promotes formation of monomeric p53 that results in its cytoplasmic translocation and subsequent loss of function. Therefore, inhibition of UBE2N may reactivate p53 by promoting its nuclear accumulation. Here, we show that NSC697923, a novel UBE2N inhibitor, exhibits potent cytotoxicity in a panel of NB cell lines evidenced by its ability to induce apoptosis. In p53 wild-type NB cells, NSC697923 induced nuclear accumulation of p53, which led to its increased transcriptional activity and tumor suppressor function. Interestingly, in p53 mutant NB cells, NSC697923 induced cell death by activating JNK pathway. This effect was reversible by blocking JNK activity with its selective inhibitor, SP600125. More importantly, NSC697923 impeded cell growth of chemoresistant LA-N-6 NB cell line in a manner greater than conventional chemotherapy drugs doxorubicin and etoposide. NSC697923 also revealed in vivo antitumor efficacy in NB orthotopic xenografts. Taken together, our results suggest that UBE2N is a potential therapeutic target in NB and provide a basis for the rational use of UBE2N inhibitors like NSC697923 as a novel treatment option for NB patients.

Download full-text

Full-text

Available from: Jed G Nuchtern, Mar 11, 2014
1 Follower
 · 
63 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: 5-FU is an anticancer drug that is widely used to treat cancers, including colorectal cancer (CRC); however, chemoresistance to 5-FU remains an important problem to be resolved. The role of microRNAs (miRs) in chemosensitivity has recently been studied in the development of therapeutic strategies to overcome drug resistance. Here, we focused on miR-96, which has been reported to demonstrate chemosensitivity. We investigated whether 5-FU sensitivity may be modulated by miR-96 in monolayer cells and whether this relationship also applies for drug resistance in 3D tumor spheroids (TSs). When the level of miR-96 increased, the expression of the anti-apoptotic regulator XIAP and p53 stability regulator UBE2N decreased, resulting in increased apoptosis and growth inhibition following 5-FU exposure. Transfection of miR-96 inhibitors resulted in an overexpression of XIAP and UBE2N, yet only minimal change was induced in apoptosis. Nonetheless, luciferase assay failed to show direct interactions between miR-96 and these genes. In TSs, 5-FU resistance corresponded to a significantly lower level of miR-96, however only XIAP, not UBE2N, was up-regulated demonstrating partial agreement with the 2D condition regarding target expression. Overall, these results suggest that miR-96 may modulate 5-FU sensitivity in CRC cells by promoting apoptosis; however, differential expression of target genes in TSs warrants further studies on the 5-FU resistance mechanism under 3D conditions.
    Archives of Pharmacal Research 12/2014; 38(2). DOI:10.1007/s12272-014-0528-9 · 1.75 Impact Factor