Therapeutic relevance of the protein phosphatase 2A in cancer

Abstract

Chromosomal Instability (CIN) is regarded as a unifying feature of heterogeneous tumor populations, driving intratumoral heterogeneity. Polo-Like Kinase 1 (PLK1), a serine-threonine kinase that is often overexpressed across multiple tumor types, is one of the key regulators of CIN and is considered as a potential therapeutic target. However, targeting PLK1 has remained a challenge due to the off-target effects caused by the inhibition of other members of the polo-like family. Here we use synthetic dosage lethality (SDL), where the overexpression of PLK1 is lethal only when another, normally non-lethal, mutation or deletion is present. Rather than directly inhibiting PLK1, we found that inhibition of PP2A causes selective lethality to PLK1-overexpressing breast, pancreatic, ovarian, glioblastoma, and prostate cancer cells. As PP2A is widely regarded as a tumor suppressor, we resorted to gene expression datasets from cancer patients to functionally dissect its therapeutic relevance. We identified two major classes of PP2A subunits that negatively correlated with each other. Interestingly, most mitotic regulators, including PLK1, exhibited SDL interactions with only one class of PP2A subunits (PPP2R1A, PPP2R2D, PPP2R3B, PPP2R5B and PPP2R5D). Validation studies and other functional cell-based assays showed that inhibition of PPP2R5D affects both levels of phospho-Rb as well as sister chromatid cohesion in PLK1-overexpressing cells. Finally, analysis of clinical data revealed that patients with high expression of mitotic regulators and low expression of Class I subunits of PP2A improved survival. Overall, these observations point to a context-dependent role of PP2A that warrants further exploration for therapeutic benefits.

Evolving Therapeutic Strategies to Exploit Chromosome Instability in Cancer

“…In this regard, a number of PARP inhibitors are currently under investigation in clinical trials aimed at assessing their utility in additional HRR-defective contexts and cancer types [ 60 ]. In addition, multiple new SL interactions were recently identified in pre-clinical studies involving various CIN genes altered in cancers, such as RAD54B , CHEK2 , BLM , PTEN, and TDP1 [ 128 , 129 , 138 , 139 , 140 ]. The SL interactors of these CIN genes are potential therapeutic targets of high interest for future CIN-exploiting therapies.…”

The prognostic value of Cyclin-Dependent Kinase 5 and Protein Phosphatase 2A in Gastric Cancer

“…Aberrant PP2A expression is associated with the occurrence and development of many malignant tumors, such as colorectal cancer, breast cancer, lung cancer and glioma 14 - 17 . Activation of PP2A can promote apoptosis, dedifferentiation and can inhibit the proliferation of tumor cells, and thus activation of PP2A is a potential target for the treatment of malignant tumors 18 , 19 . Louis et al 20 Found that a knockout of the PP2A subunit (Ppp2r5d) in mice could affect the activities of CDK5 and GSK-3β, decrease the activity of CDK5 phosphatase and increase the activity of GSK-3β, which lead the to the development of space restricted tau disease in these knockout mice.…”

Targeting PP2A activates AMPK signaling to inhibit colorectal cancer cells

“…Recently, colorectal cancer (CRC) studies have been focusing on molecule-targeted therapy [ 1 , 2 ] and exploring novel chemo-preventive agents [ 3 – 6 ]. Protein phosphatase 2A (PP2A) is a well-established serine/threonine phosphatase [ 7 – 9 ], which is extremely important in regulation of mitotic progression and DNA damage responses [ 10 ]. Although PP2A was traditionally viewed as a tumor suppressor [ 10 , 11 ], recent cancer studies have indicated that PP2A inhibition could inhibit cancer cells via driving senescent cancer cells into mitosis or promoting cancer cell death and apoptosis [ 12 , 13 ].…”