Altering phosphorylation in cancer through PP2A modifiers

Abstract

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase integral to the regulation of many cellular processes. Due to the deregulation of PP2A in cancer, many of these processes are turned toward promoting tumor progression. Considerable research has been undertaken to discover molecules capable of modulating PP2A activity in cancer. Because PP2A is capable of immense substrate specificity across many cellular processes, the therapeutic targeting of PP2A in cancer can be completed through either enzyme inhibitors or activators. PP2A modulators likewise tend to be effective in drug-resistant cancers and work synergistically with other known cancer therapeutics. In this review, we will discuss the patterns of PP2A deregulation in cancer, and its known downstream signaling pathways important for cancer regulation, along with many activators and inhibitors of PP2A known to inhibit cancer progression.

Keywords: Activators; Cancer; Inhibitors; PP2A; Therapeutics.

Fig. 1

Overview of the downstream effects of PP2A therapeutics. Indirect PP2A activators inhibit the endogenous protein inhibitors of PP2A resulting in increased PP2A activation and increased regulation of downstream pathways, such as Wnt/β-catenin, PI3K/Akt, and MAPK. Direct PP2A activators can bind directly to the protein and promote its activation leading to increased regulation of pathways involved in tumor progression. PP2A inhibitors can bind to the protein and prevent dephosphorylation of its substrates leading to increased cell cycle progression and eventually cell death due to DNA damaged cancer cells

Fig. 2

A PP2A-B56⍺ dephosphorylates mTOR downregulating its activity. mTOR, alternatively, can inhibit PP2A leading to dephosphorylation of IRS1. p-IRS1 activates PI3K/Akt signaling leading to increased protein synthesis. B Some of the PP2A-B56⍺ downstream signaling. 56⍺ dephosphorylates GSK-3β activating it and allowing GSK-3β to phosphorylate β-catenin resulting in ubiquitin tagging for degradation in the ubiquitin–proteasome pathway. B56⍺ also dephosphorylates c-Myc resulting in it being tagged by ubiquitin for degradation. PP2A-B56⍺ can also dephosphorylate Akt, inhibiting mTORC1, and resulting in the inhibition of translation and the cell cycle progression. C PP2A-B55⍺, on the other hand, can dephosphorylate β-catenin allowing it to activate the Wnt responsive genes (WRE) and transcribe the Cyclin D1 and c-Myc. B55⍺ dephosphorylates KSR1 causing its disassociation from the 14-3-3 complex and binding to the RAS-RAF complex, which phosphorylates MEK1. Activated MEK1 then phosphorylates ERK1/2 activating it for downstream regulation. PP2A-B56β/γ is the subunit known to dephosphorylate ERK1/2 reversing these activations

Fig. 3

Chemical structures of the PP2A modulators. MarvinSketch was used for drawing chemical structures, Marvin 17.21.0, Chemaxon (https://www.chemaxon.com)