Targeting the Ubiquitin-Mediated Proteasome Degradation of p53 for Cancer Therapy

Abstract

Within the past decade, there has been a revolution in the types of drugs developed to treat cancer. Therapies that selectively target cancer-specific aberrations, such as kinase inhibitors, have made a dramatic impact on a subset of patients. In spite of these successes, there is still a dearth of treatment options for the vast majority of patients. Therefore, there is a need to design therapies with broader efficacy. The p53 tumor suppressor pathway is one of the most frequently altered in human cancers. However, about half of all cancers retain wild-type p53, yet through various mechanisms, the p53 pathway is otherwise inactivated. Targeting this pathway for reactivation truly represents the “holy grail” in cancer treatment. Most commonly, destabilization of p53 by various components of ubiquitin-proteasome system, notably the ubiquitin ligase MDM2 and its partner MDMX as well as various deubiquitinating enzymes (DUBs), render p53 inert and unresponsive to stress signals. Reinstating its function in cancer has been a long sought-after goal. Towards this end, a great deal of work has been devoted to the development of compounds that either interfere with the p53-MDM2 and p53-MDMX interactions, inhibit MDM2 E3 activity, or target individual DUBs. Here we review the current progress that has been made in the field, with a special emphasis on both MDM2 and DUB inhibitors. Developing inhibitors targeting the upstream of the p53 ubiquitination pathway will likely also be a valuable option.

Genomic Copy Number Alterations in Serous Ovarian Cancer

“…This suggests that not only is the core recycling process partly compromised by the core component deletions, but that the pathway is redirected to allow for cell cycle progression proteins to persist and push the cell through division. The latter finding is perhaps to be expected, given that this has been established as a mechanism for tumor formation in many reviews [86][87][88]. Yet the proteasome may have a similar function to autophagy in suppressing aneuploidy.…”

MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53

“…MDM2 is a major ubiquitin ligase that cooperates with MDM4 to degrade TP53 via the ubiquitin-proteasome system [21, 32, 33]. MDM2 is negatively regulated by specific microRNAs such as miR-1827 and miR-340 [34–36], and overexpression via multiple mechanisms is observed in various types of human malignancies, including sarcomas, gliomas, hematological malignancies, and breast cancer [34, 37].…”

Suberoyl bis-hydroxamic acid activates Notch1 signaling and induces apoptosis in anaplastic thyroid carcinoma through p53

“…p53 actively promotes apoptosis and plays a key role in controlling tumor growth (33), and its transcriptional function is considered as a marker of large-scale differently expressed genes and involved in cell cycle arrest, which are the main causes of cell apoptosis (34). There are many conflicting conclusions on the reciprocal relationship between Notch signaling and p53 function.…”