Neuroblastoma: oncogenic mechanisms and therapeutic exploitation of necroptosis

Abstract

Neuroblastoma (NB) is the most common extracranial childhood tumor classified in five stages (1, 2, 3, 4 and 4S), two of which (3 and 4) identify chemotherapy-resistant, highly aggressive disease. High-risk NB frequently displays MYCN amplification, mutations in ALK and ATRX, and genomic rearrangements in TERT genes. These NB subtypes are also characterized by reduced susceptibility to programmed cell death induced by chemotherapeutic drugs. The latter feature is a major cause of failure in the treatment of advanced NB patients. Thus, proper reactivation of apoptosis or of other types of programmed cell death pathways in response to treatment is relevant for the clinical management of aggressive forms of NB. In this short review, we will discuss the most relevant genomic rearrangements that define high-risk NB and the role that destabilization of p53 and p73 can have in NB aggressiveness. In addition, we will propose a strategy to stabilize p53 and p73 by using specific inhibitors of their ubiquitin-dependent degradation. Finally, we will introduce necroptosis as an alternative strategy to kill NB cells and increase tumor immunogenicity.

Roles of p21, p53, cyclin D1, CDK‐4, estrogen receptor α in aflatoxin B1‐induced cytotoxicity in testicular tissue of mice

“…Actually, the p21 negatively regulates the p53‐dependent and/or independent apoptosis pathways by interacting with Cdk4 . However, it has been illustrated that progressive DNA damage can trigger p53 overexpression, which in turn initiates the p53‐mdiated apoptosis pathway independent to p21 overexpression . Actually in a case, the p53 induces transcriptional activation of pro‐apoptotic factors such as FAS, PUMA, and BAX .…”

Cell Proliferation in Neuroblastoma

“…Mutations in the tumor suppressor, P53, are the most frequent genetic alterations found in human cancer [ 56 ]. Mutations in P53 are infrequent in neuroblastoma and are mostly limited to relapsed tumors [ 57 , 58 , 59 , 60 ], but wild-type P53 is often destabilized and not functional. In undifferentiated neuroblastomas, wild-type P53 was sequestered in the cytoplasm preventing its function as a transcription factor [ 61 ].…”

WHICH WAY DO YOU PREFER TO DEATH ? Cell Death and Beyond

“…Necroptosis is highly pro-inflammatory owing to the release of pro-inflammatory cytokines and damage associated molecular patterns [259]. Necroptosis occurs in the absence of caspase activity and is regulated by the activity of a multi-protein complex called necrosome [260]. Necroptosis engages of the extrinsic pathway in the absence of caspase-8 can result in a necrotic cell.…”