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Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutic options
Godfrey Grech1, Shawn Baldacchino2, Christian Saliba3
1Department of Pathology, Faculty of Medicine & Surgery, Medical School, University of Malta, Msida, MSD2090, Malta. godfrey.grech@um.edu.mt.
Abstract:
The complexity of the phosphatase, PP2A, is being unravelled and current research is increasingly providing information on the association of deregulated PP2A function with cancer initiation and progression. It has been reported that decreased activity of PP2A is a recurrent observation in many types of cancer, including colorectal and breast cancer (Baldacchino et al. EPMA J. 5:3, 2014; Cristobal et al. Mol Cancer Ther. 13:938-947, 2014). Since deregulation of PP2A and its regulatory subunits is a common event in cancer, PP2A is a potential target for therapy (Baldacchino et al. EPMA J. 5:3, 2014). In this review, the structural components of the PP2A complex are described, giving an in depth overview of the diversity of regulatory subunits. Regulation of the active PP2A trimeric complex, through phosphorylation and methylation, can be targeted using known compounds, to reactivate the complex. The endogenous inhibitors of the PP2A complex are highly deregulated in cancer, representing cases that are eligible to PP2A-activating drugs. Pharmacological opportunities to target low PP2A activity are available and preclinical data support the efficacy of these drugs, but clinical trials are lacking. We highlight the importance of PP2A deregulation in cancer and the current trends in targeting the phosphatase.
Insights
Decreased protein phosphatase 2A (PP2A) activity is common in cancers. Targeting PP2A reactivation offers a promising therapeutic strategy, though clinical trials are needed.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Deregulation of protein phosphatase 2A (PP2A) is implicated in cancer initiation and progression.
- Reduced PP2A activity is a recurring hallmark across various cancer types, including colorectal and breast cancer.
- PP2A's central role in cellular processes makes its deregulation a significant factor in tumorigenesis.
Purpose of the Study:
- To review the structural components and regulatory subunits of the PP2A complex.
- To explore the mechanisms of PP2A regulation, including phosphorylation and methylation.
- To discuss the therapeutic potential of targeting PP2A activity in cancer treatment.
Main Methods:
- Literature review of PP2A structure, function, and regulation.
- Analysis of PP2A's role in cancer based on existing research.
- Overview of current and potential pharmacological strategies for PP2A reactivation.
Main Results:
- PP2A comprises diverse regulatory subunits, influencing its complex structure.
- Phosphorylation and methylation are key regulatory mechanisms of PP2A activity.
- Endogenous PP2A inhibitors are frequently deregulated in cancer, creating therapeutic opportunities.
Conclusions:
- Targeting PP2A reactivation through pharmacological intervention is a viable therapeutic avenue.
- Preclinical data support the efficacy of PP2A-activating drugs.
- Further clinical trials are necessary to validate the therapeutic potential of targeting PP2A in cancer patients.
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