Non-genomic mechanisms of protein phosphatase 2A (PP2A) regulation in cancer

Kauko, Otto; Westermarck, Jukka

doi:10.1016/j.biocel.2018.01.005

Cited by 95 publications

(110 citation statements)

References 151 publications

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“…These results provide the first indications that PP2A reactivation might be able to challenge the current paradigm in GB therapies which has been strongly focused on targeting specific genetically altered cancer drivers with highly specific inhibitors (Verhaak et al, 2010;Barretina et al, 2012;Brennan et al, 2013). PP2A is known to simultaneously target a number of cancer driver pathways and pro-apoptotic mechanisms (Perrotti and Neviani, 2013;Kauko and Westermarck, 2018). We envision that these wide-spectrum effects may explain the very robust preclinical survival effects across kinase inhibitor resistant cell lines harboring heterogenous genetic drivers.…”

Section: Dbk-1154 With Higher Degree Of Brain/blood Distribution Anmentioning

confidence: 81%

“…Frequency of genetic mutations or deletions in any of the genes coding for core PP2A complex components in GB clinical isolates is negligible (Kaur et al, 2016). However, we found that all studied GB cell lines expressed higher levels of PP2A inhibitor proteins (PAIPs); PME-1, CIP2A, SET, and ARPP-19 (Kauko and Westermarck, 2018), as compared to non-tumor fibroblasts ( Fig. 2A).…”

Section: Nz-8-061 Potently Inhibits the Viability Of Gb Cells With Hementioning

confidence: 88%

“…Notably, phosphorylation of GB driver pathways is not only regulated by kinases, but also by phosphatases (Narla et al, 2018;. Amongst them, Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that regulates multiple oncogenic kinase signaling pathways, as well as apoptotic mechanisms (Perrotti and Neviani, 2013;Kauko and Westermarck, 2018). Interestingly, because PP2A is not genetically inactivated in GB (Kaur et al, 2016), it could be a suitable target for tumor suppressor reactivation therapies in this medically challenging indication.…”

Section: Introductionmentioning

confidence: 99%

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Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

Merisaari

Denisova

Doroszko

et al. 2019

Preprint

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Glioblastoma (GB) is a fatal disease in which most targeted therapies have clinically failed.However, pharmacological reactivation of tumor suppressors has not been thoroughly studied as yet as a GB therapeutic strategy. Tumor suppressor Protein Phosphatase 2A (PP2A), is inhibited by non-genetic mechanisms in GB, and thus it would be potentially amendable for therapeutic reactivation. Here we demonstrate, that small molecule activators of PP2A (SMAPs), NZ-8-061and DBK-1154, effectively cross the in vitro model of blood-brain barrier (BBB), and in vivo partition to mouse brain tissue after oral dosing. In vitro, SMAPs exhibit robust cell killing activity against five established GB cell lines, and nine patient-derived primary glioma cell lines.Collectively these cell lines have heterogenous genetic background, kinase inhibitor resistance profile, and stemness properties; and they represent different clinical GB subtypes. Oral dosing of either of the SMAPs significantly reduced growth of infiltrative intracranial GB tumors. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested GB cell lines, also significantly increased survival of mice bearing orthotopic GB xenografts. In summary, this report presents a proof-of-principle data for BBB-permeable tumor suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background.

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Section: Dbk-1154 With Higher Degree Of Brain/blood Distribution Anmentioning

confidence: 81%

Section: Nz-8-061 Potently Inhibits the Viability Of Gb Cells With Hementioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

Merisaari

Denisova

Doroszko

et al. 2019

Preprint

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“…1A) in which a core dimer formed between the scaffolding A subunit (PPP2R1A, PPP2R1B) and the catalytic C subunit (PPP2CA, PPP2CB) is associated with one of the many B subunits that facilitate and direct the interaction of the trimer with substrate proteins 16 . In addition to mutations found in cancer, PP2A activity is regulated by various nongenomic mechanisms 18 including post-translational modifications of PP2A complex components, as well as by interaction with group of designated PP2A inhibitor proteins (PIPs hereafter). The best-characterized PIPs are CIP2A, PME-1, and SET ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Rules for PP2A-controlled phosphosignalling and drug responses

Kauko

Imanishi

Kulesskiy

et al. 2018

Preprint

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Systemic understanding of protein phosphatase 2A (PP2A)-regulated cellular processes is still at infancy. Here, we present mass-spectrometry analysis of phospho-targets (dephosphorylome) regulated by PP2A modulation. In addition to PP2A-regulated processes and targets, the data reveal important general concepts and rules related to PP2A-mediated phosphoregulation.These include the unidirectionality paradigm of regulation of phosphorylation, and differential spatial distribution of kinase-and phosphatase-dominated phosphotargets. Data also present first systemic analysis of targets of PP2Amodulating oncoproteins, CIP2A, PME-1, and SET; including targets via which PP2A may coordinately regulate activities of cancer drivers and tumor suppressors such as MYC or TP53. To validate functional utility of this dataset, PP2A dephosphorylome activity was correlated with cancer cell responses to over 300 drugs. Notably, we find that cancer therapy responses can be broadly classified based on PP2A dephosphorylome activity, both in quantitative and qualitative manner. In summary, our data characterize rules by which PP2A coordinate cancer cell phosphosignaling and drug responses. The results also may also direct the use of emerging pharmacological approaches for PP2A activity modulation in human diseases.

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“…Ppp2r1a was downregulated by simvastatin compared with the CM group, but was upregulated in the SIM + Cpn group compared with the SIM group. Ppp2r1a encodes a structural subunit A of protein phosphatase 2A (PP2A), which is a principal Ser/Thr phosphatase that functions as an antagonist of many signaling pathways associated with growth and proliferation . Notably, PP2A participates in complex negative feedback regulation by oncogenic pathways related to proliferation, and plays an important role in MAPK and JAK/STAT signaling …”

Section: Discussionmentioning

confidence: 99%

Identification of Gli1‐interacting proteins during simvastatin‐stimulated osteogenic differentiation of bone marrow mesenchymal stem cells

Chi

Fan

et al. 2019

J of Cellular Biochemistry

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Simvastatin has been shown to promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Our study aimed to illuminate the underlying mechanism, with a specific focus on the role of Hedgehog signaling in this process. BMSCs cultured with or without 10−7 mol/L simvastatin were subjected to evaluation of osteogenic differentiation capacity. Osteogenic markers such as type 1 collagen (COL1) and osteocalcin (OCN), as well as key molecules of Hedgehog signaling molecules, were examined by Western blot and real‐time polymerase chain reaction (PCR). Co‐immunoprecipitation and mass spectrometry assays were applied to screen for Gli1‐interacting proteins. Cyclopamine (Cpn) was used as a Hedgehog signaling inhibitor. Our results indicated that simvastatin increased alkaline phosphatase (ALP) activity; mineralization of extracellular matrix; mRNA expression of ALP, COL1, and OCN; and expression and nuclear translocation of Gli1. Contrasting effects were observed in Cpn‐exposed groups, but were partially rescued by the simvastatin treatment. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that Gli1‐interacting proteins were primarily associated with mitogen‐activated protein kinase (MAPK) (P = 7.04E−04), hippo, insulin, and glucagon signaling. Further, hub genes identified by protein‐protein interaction network analysis included Gli1‐interacting proteins such as Ppp2r1a, Rac1, Etf1, and XPO1/CRM1. In summary, the current study showed that the mechanism by which simvastatin stimulates osteogenic differentiation of BMSCs involves activation of Hedgehog signaling, as indicated by interactions with Gli1 and, most notably, the MAPK signaling pathway.

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Non-genomic mechanisms of protein phosphatase 2A (PP2A) regulation in cancer

Cited by 95 publications

References 151 publications

Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

Monotherapy efficacy of BBB-permeable small molecule activators of PP2A in glioblastoma

Rules for PP2A-controlled phosphosignalling and drug responses

Identification of Gli1‐interacting proteins during simvastatin‐stimulated osteogenic differentiation of bone marrow mesenchymal stem cells

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