Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutic options

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.

Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial

“…Our hypothesis is that tumors sensitive to PPA inhibition have acquired defects in PP2A activity or regulation that make them more vulnerable to pharmacologic inhibition of PP2A than normal cells. There is a large and growing body of evidence that endogenous inhibitors of PP2A, especially the SET/I2PP2A and CIP2A oncoproteins, are overexpressed in and responsible for reduced PP2A activity in many types of solid tumors and acute and chronic myeloid leukemias (8,(24)(25)(26). Several groups are pursuing pharmacologic means to either inhibit SET or increase PP2A as treatment for such cancers (27)(28)(29)(30)(31)(32).…”

The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives

“…Another target of fingolimod in cancer is PP2A, a tumor suppressor with decreased activity in various human tumors (Cristobal et al, 2016;Grech et al, 2016;Perrotti et al, 2013).…”

Metabolic signaling functions of ER–mitochondria contact sites: role in metabolic diseases

“…4). Indeed, reduced PP2A activity has been observed in Alzheimer's disease (Sontag & Sontag 2014) and in cancers (Grech et al 2016), whereas an increased expression of the catalytic subunit of PP2A has been observed after viral infection (Tsunematsu et al 2016). Until now, no link has been made between PP2A and WFS.…”