Protein phosphatase 2A: a target for anticancer therapy

Abstract

Protein phosphatase 2A (PP2A), one of the main serine-threonine phosphatases in mammalian cells, maintains cell homoeostasis by counteracting most of the kinase-driven intracellular signalling pathways. Unrestrained activation of oncogenic kinases together with inhibition of tumour suppressors is often required for development of cancer. PP2A has been shown to be genetically altered or functionally inactivated in many solid cancers and leukaemias, and is therefore a tumour suppressor. For example, the phosphatase activity of PP2A is suppressed in chronic myeloid leukaemia and other malignancies characterised by aberrant activity of oncogenic kinases. Preclinical studies show that pharmacological restoration of PP2A tumour-suppressor activity by PP2A-activating drugs (eg, FTY720) effectively antagonises cancer development and progression. Here, we discuss PP2A as a druggable tumour suppressor in view of the possible introduction of PP2A-activating drugs into anticancer therapeutic protocols.

Figure 1. Physiological functions of PP2A

Schematic representation of some of the pathways controlled by PP2A. The figure shows the many levels at which PP2A affects the normal physiology of cells. PP2A, by virtue of its phosphatase activity counteracts most of the signal triggered by protein kinases.

Figure 2. Opposing roles of PP2A and BCR-ABL1 in CML

Schematic representation of the major targets of BCR-ABL1, whose activity is counteracted by the phosphatase activity of PP2A. In CML, PP2A is inhibited in a SET/JAK2/CIP2A dependent manner. PP2A, when active, targets most of the downstream effectors of BCR-ABL1 and can also induce BCR-ABL1 inactivation/degradation through the Shp-1 tumor suppressor phosphatase.