Modulation of serine/threonine-protein phosphatase 1 (PP1) complexes: A promising approach in cancer treatment

Highlights

• The development of new and optimized anticancer therapies is an urgent requirement.

• Serine/threonine-protein phosphatase 1 (PP1) has been recognized as a potential drug target in cancer.

• Several PP1 complexes have been characterized in cancer models.

• The disruption or stabilization of PP1 complexes offer advantages in cancer treatment.

Abstract

Cancer is the second leading cause of death worldwide. Despite the availability of numerous therapeutic options, tumor heterogeneity and chemoresistance have limited the success of these treatments, and the development of effective anticancer therapies remains a major focus in oncology research. The serine/threonine-protein phosphatase 1 (PP1) and its complexes have been recognized as potential drug targets. Research on the modulation of PP1 complexes is currently at an early stage, but has immense potential. Chemically diverse compounds have been developed to disrupt or stabilize different PP1 complexes in various cancer types, with the objective of inhibiting disease progression. Beneficial results obtained in vitro now require further pre-clinical and clinical validation. In conclusion, the modulation of PP1 complexes seems to be a promising, albeit challenging, therapeutic strategy for cancer.

Introduction

According to the World Health Organization (WHO), cancer is considered a major public health concern, estimated to be the second leading cause of death worldwide. The incidence of cancer has increased latterly, with a total of 18.1 million new cases and 9.6 million deaths reported globally in 2018.¹ At present, therapy decisions are dictated by cancer type and clinical staging. Options include both localized therapies, including surgery or radiation therapy, and systemic therapies that encompass chemotherapy and hormonal or immune interventions. The success of conventional therapies is essentially limited by tumor heterogeneity and their acquired resistance to therapy.² In the past decade, important advances have been provided by increasingly detailed knowledge of the molecular biology of tumors, coupled with the emergence of new approaches for cancer treatment such as more personalized cancer medicine. Nevertheless, serious challenges remain and the establishment of improved therapies is urgently needed.²

Interventions that target the post-translational phosphorylation of intracellular proteins have been considered as viable anticancer therapies. Transient phosphorylation events control most cellular signaling processes, and abnormal phosphorylation profiles have been associated with several pathological conditions, including cancers.³ The phosphoproteome is formed by the activities of both protein kinases and phosphatases, which add or remove phosphate groups, respectively. The balance between the activities of these two types of enzyme is essential to maintain cellular homeostasis.⁴ Thus, the targeting of both protein kinases and protein phosphatases has been proposed for cancer treatment.5., 6.

Serine/threonine-protein phosphatase 1 (PP1) is a major protein phosphatase, which catalyzes a wide range of protein dephosphorylation reactions in human cells.⁷ It regulates critical cellular processes including cell cycle progression, apoptosis and metabolism.⁸ The involvement of PP1 in several oncogenic pathways has become evident, and its expression level seems to be altered in the presence of a tumor.⁹ Nevertheless, the direction in which PP1 expression levels are altered is not clear as contradictory results have been published. Importantly, PP1 deregulation seems to depend on the type of cancer, on the interacting proteins and on the PP1 isoform.10., 11., 12., 13. Indeed, the catalytic subunit of PP1 (PP1c) is encoded by three genes (PPP1CA, PPP1CB and PPP1CC), which give rise to three different isoforms (PP1-alpha catalytic subunit (PP1α), PP1-beta catalytic subunit (PP1β) and PP1-gamma catalytic subunit (PP1ϒ)) that are ubiquitously expressed and differ mainly in their extremities.¹⁴ The roles of PP1 depend on the interaction of PP1c with different regulatory interactors of PP1 (RIPPOs)¹⁵ (previously called PP1-interacting proteins (PIPs)), which can act as targeting subunits, substrates, activity regulators, or through a combination of these roles. A determined effort over several decades has identified the PP1c interactome in different tissues and specific biological contexts, including pathological conditions.16., 17., 18., 19. Despite the relatively high number of PP1 complexes identified in human tissues, the highly dynamic nature of these complexes has clearly hampered their functional characterization.²⁰

Targeting of PP1 has been considered for the treatment of several other diseases, including heart failure²¹ and neurological conditions.²² Compared with conventional chemotherapies, interventions that modulate discrete PP1 complexes could provide a more specific option with reduced cytotoxicity. In fact, this novel approach has been proposed for the treatment of various pathologies,23., 24., 25. including cancer.

In this context, we rigorously reviewed the potential of modulating PP1 complexes in cancer treatment. Herein, we summarize the PP1 complexes characterized in different types of cancer, highlighting their roles as tumor promoters or suppressors. The PP1 complexes that are modulated by either small molecules or peptides in cancer are also described. Finally, we define the main conclusions that can be drawn from the studies, and the principal challenges to be addressed by future work in this topic.