The broken “Off” switch in cancer signaling: PP2A as a regulator of tumorigenesis, drug resistance, and immune surveillance

Abstract

Aberrant activation of signal transduction pathways can transform a normal cell to a malignant one and can impart survival properties that render cancer cells resistant to therapy. A diverse set of cascades have been implicated in various cancers including those mediated by serine/threonine kinases such RAS, PI3K/AKT, and PKC. Signal transduction is a dynamic process involving both “On” and “Off” switches. Activating mutations of RAS or PI3K can be viewed as the switch being stuck in the “On” position resulting in continued signaling by a survival and/or proliferation pathway. On the other hand, inactivation of protein phosphatases such as the PP2A family can be seen as the defective “Off” switch that similarly can activate these pathways. A problem for therapeutic targeting of PP2A is that the enzyme is a hetero-trimer and thus drug targeting involves complex structures. More importantly, since PP2A isoforms generally act as tumor suppressors one would want to activate these enzymes rather than suppress them. The elucidation of the role of cellular inhibitors like SET and CIP2A in cancer suggests that targeting these proteins can have therapeutic efficacy by mechanisms involving PP2A activation. Furthermore, drugs such as FTY-720 can activate PP2A isoforms directly. This review will cover the current state of knowledge of PP2A role as a tumor suppressor in cancer cells and as a mediator of processes that can impact drug resistance and immune surveillance.

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 mechanism by which the inhibition of PP2A results in the inhibition of transformed cells of a variety of cell types was puzzling, as PP2A has been considered a tumor suppressor. Chemical inhibitors of PP2A, most notably okadaic acid, and transforming viral antigens Simian virus 40 small T antigen and murine polyoma virus middle T antigen were shown to inhibit PP2A activity as part of the transformation process (2,(6)(7)(8).…”

Roles and regulation of protein phosphatase 2A (PP2A) in the heart

“…Notably, over half the proteins in human cells have the capacity to undergo reversible phosphorylation, highlighting the potential importance of phosphorylation pathways [10]. The critical roles of phosphorylation for physiologic regulation of various cell and tissue types have been reviewed many times over [11–15]. …”

Definition of the fibroblast adhesome using multiplexed proximity biotinylation

“…PTP-PEST was also identified as a proximal interactor by BirA*vinculin, -ILK and -GIT1, though these proteins have not been identified as substrates for PTP-PEST, and may represent indirect interactors. Ppp2r3a, a regulatory subunit of the serine threonine phosphatase heterotrimer PP2A, is part of the PR72/PR130 subgroup of PP2A isoforms 74 . Recently, ppp2r3a was shown to regulate cell migration via interaction with LPP LIM domains 75 .…”