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

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.

mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling

“…We then assumed that INK128 might help overcome chemoresistance in neuroblastoma. Based on previous reports, LA-N-6 cells are resistant to a much higher dose of Dox compared to other neuroblastoma cells tested [18, 19]. However, co-culture of LA-N-6 cells with mTOR inhibitor INK128 significantly increased the sensitivity of LA-N-6 cells to Dox (Fig.…”

Proteomics analysis of malignant and benign prostate tissue by 2D DIGE/MS reveals new insights into proteins involved in prostate cancer

“…Ubiquitin‐conjugating enzyme E2N (UBE2N) plays a role in the error‐free DNA repair pathway and contributes to the survival of cells after DNA damage . It has been found up‐regulated in various cancers such as triple‐negative breast cancer , neuroblastoma , diffuse large B‐cell lymphoma , and colon cancer cell HCT‐15 . Recently, the role of UBE2N in neuroblastoma development was explained by p53 inactivation through formation of monomeric p53 that results in its cytoplasmic translocation and subsequent loss of function .…”

Amino-terminal residues of ΔNp63, mutated in ectodermal dysplasia, are required for its transcriptional activity

“…This complexity raise from different angles, including for example its stability and degradation [32,33], its connection to micro-RNA [34,35] or its splicing isoforms [36,37]. In keeping with the progress in understanding p53 biology, significant progress is also under way on its potential therapeutic application [38,39]. Although being identified much later, already now, p63 and p73 show their complexity and interaction with p53 [40e42]; where p63 function is highly relevant in skin formation and homeostasis [43] as well as in cancer [41,44].…”