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Published on: May 10, 2022
Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention
1Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
Abstract:
The ubiquitin proteasome system (UPS) governs the non-lysosomal degradation of oxidized, damaged, or misfolded proteins in eukaryotic cells. This process is tightly regulated through the activation and transfer of polyubiquitin chains to target proteins which are then recognized and degraded by the 26S proteasome complex. The role of UPS is crucial in regulating protein levels through degradation to maintain fundamental cellular processes such as growth, division, signal transduction, and stress response. Dysregulation of the UPS, resulting in loss of ability to maintain protein quality through proteolysis, is closely related to the development of various malignancies and tumorigenesis. Here, we provide a comprehensive general overview on the regulation and roles of UPS and discuss functional links of dysregulated UPS in human malignancies. Inhibitors developed against components of the UPS, which include U.S. Food and Drug Administration FDA-approved and those currently undergoing clinical trials, are also presented in this review.
Insights
The ubiquitin proteasome system (UPS) degrades damaged proteins, crucial for cell health. Its dysregulation links to cancer, and UPS inhibitors are key cancer therapeutics.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- The ubiquitin proteasome system (UPS) is essential for degrading damaged or misfolded proteins in eukaryotic cells.
- This regulated process maintains cellular homeostasis by controlling protein levels.
- UPS dysfunction is implicated in various human malignancies.
Purpose of the Study:
- To provide a comprehensive overview of UPS regulation and function.
- To discuss the role of UPS dysregulation in human cancers.
- To review current and investigational UPS inhibitors for cancer therapy.
Main Methods:
- Literature review of UPS regulation, function, and dysregulation in cancer.
- Analysis of the role of proteolysis in cellular processes.
- Compilation of information on FDA-approved and clinical trial UPS inhibitors.
Main Results:
- The UPS tightly regulates protein degradation via polyubiquitin chains and the 26S proteasome.
- UPS dysregulation contributes to tumorigenesis and cancer development.
- Numerous UPS inhibitors are in clinical trials, with some FDA-approved, targeting cancer.
Conclusions:
- The UPS is a critical regulator of cellular protein quality control.
- Targeting the UPS holds significant therapeutic potential for treating human malignancies.
- Understanding UPS pathways is vital for developing novel cancer treatments.
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