Inhibition of protein phosphatase-1 and -2A decreases the chemosensitivity of leukemic cells to chemotherapeutic drugs

Dedinszki, Dóra; Kiss, Andrea; Márkász, László; Márton, Adrienn; Tóth, Emese; Szekeres, L.; Erdõdi, Ferenc

doi:10.1016/j.cellsig.2014.11.021

Cited by 22 publications

(24 citation statements)

References 44 publications

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“…CLA decreased the phosphatase activity of the lysate by ~25%, and a large portion (~20%) of this inhibitory impact was exerted on the I2 suppressed (i.e. PP2A) activity indicating predominant inhibition of PP2A by CLA in accord with our previous findings31 in THP-1 cells.…”

Section: Resultssupporting

confidence: 90%

“…CLA and TM inhibit both PP2A and PP1 in in vitro phosphatase assays and there are also controversies concerning their selectivity in cellular systems2930. However, our recent results31 confirmed that CLA (up to 50 nM) caused partial, but predominant inhibition of PP2A, while TM (up to 1 μM) primarily suppressed PP1 in THP-1 cells. Figure 5a illustrates that treatment of BPAECs with CLA alone resulted in a dramatic increase in the phosphorylation of MYPT1 at Thr696 (MYPT1 pThr696 ) while TM and PMA did not increase significantly the level of MYPT1 pThr696 .…”

Section: Resultsmentioning

confidence: 51%

“…In this study regulation of eNOS pThr497 level by MP was modelled using cell permeable phosphatase inhibitory toxins (CLA and TM) at concentrations assumed to be specific for PP1 and PP2A293031. It should be emphasized that the viability of ECs limits the applied toxin concentrations, therefore, only partial inhibition of PP2A or PP1 by these toxins could be assumed as we showed previously31.…”

Section: Discussionmentioning

confidence: 91%

“…It has been established that regulation of MP activity occurs via inhibitors (toxins, inhibitory proteins) interacting with PP1cδ222331 and/or by inhibitory phosphorylation of MYPT1 at Thr696 and Thr850 residues41. In this study regulation of eNOS pThr497 level by MP was modelled using cell permeable phosphatase inhibitory toxins (CLA and TM) at concentrations assumed to be specific for PP1 and PP2A293031.…”

Section: Discussionmentioning

confidence: 99%

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Interplay of myosin phosphatase and protein phosphatase-2A in the regulation of endothelial nitric-oxide synthase phosphorylation and nitric oxide production

Bátori

Bécsi

Nagy

et al. 2017

Sci Rep

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The inhibitory phosphorylation of endothelial nitric oxide (NO) synthase (eNOS) at Thr497 (eNOSpThr497) by protein kinase C or RhoA-activated kinase is a major regulatory determinant of eNOS activity. The signalling mechanisms involved in the dephosphorylation of eNOSpThr497 have not yet been clarified. This study identifies myosin phosphatase (MP) holoenzyme consisting of protein phosphatase-1 catalytic subunit (PP1c) and MP target subunit-1 (MYPT1) as an eNOSpThr497 phosphatase. In support of this finding are: (i) eNOS and MYPT1 interacts in various endothelial cells (ECs) and in in vitro binding assays (ii) MYPT1 targets and stimulates PP1c toward eNOSpThr497 substrate (iii) phosphorylation of MYPT1 at Thr696 (MYPT1pThr696) controls the activity of MP on eNOSpThr497. Phosphatase inhibition suppresses both NO production and transendothelial resistance (TER) of ECs. In contrast, epigallocatechin-3-gallate (EGCG) signals ECs via the 67 kDa laminin-receptor (67LR) resulting in protein kinase A dependent activation of protein phosphatase-2A (PP2A). PP2A dephosphorylates MYPT1pThr696 and thereby stimulates MP activity inducing dephosphorylation of eNOSpThr497 and the 20 kDa myosin II light chains. Thus an interplay of MP and PP2A is involved in the physiological regulation of EC functions implying that an EGCG dependent activation of these phosphatases leads to enhanced NO production and EC barrier improvement.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Interplay of myosin phosphatase and protein phosphatase-2A in the regulation of endothelial nitric-oxide synthase phosphorylation and nitric oxide production

Bátori

Bécsi

Nagy

et al. 2017

Sci Rep

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“…PP2A inhibitors including LB-100 and calyculin A have been evaluated as sensitizers for chemotherapy or radiotherapy in several malignancies. [48][49][50] Cantharidin, another PP2A inhibitor, suppresses the migration and growth of pancreatic and breast cancer cells. 48,[51][52][53] We also previously reported that OA induced apoptosis in several types of cell line including osteosarcoma cells through NF-κB and PKR pathways.…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 2A Cα regulates proliferation, migration, and metastasis of osteosarcoma cells

Yang

Okamura

Morimoto

et al. 2016

Laboratory Investigation

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Osteosarcoma is the most frequent primary bone tumor. Serine/threonine protein phosphatase 2A (PP2A) participates in regulating many important physiological processes, such as cell cycle, growth, apoptosis, and signal transduction. In this study, we examined the expression and function of PP2A Cα in osteosarcoma cells. PP2A Cα expression was expected to be higher in malignant osteosarcoma tissues. PP2A Cα expression level and PP2A activity was higher in malignant osteosarcoma LM8 cells compared with that in primary osteoblasts and in the osteoblast-like cell line MC3T3-E1. Okadaic acid, an inhibitor of PP2A, reduced cell viability and induced apoptosis in LM8 cells. PP2A Cα-knockdown LM8 cells (shPP2A) exhibited less striking filopodial and lamellipodial structures than that in original LM8 cells. Focal adhesion kinase phosphorylation and NF-κB activity decreased in shPP2A-treated cells. Sensitivity to serum deprivation-induced apoptosis increased in shPP2A-treated cells, accompanied by a lower expression level of anti-apoptotic BCL-2 in these cells. Reduction of PP2A Cα resulted in a decrease in the migration ability of LM8 cells in vitro. Reduction in PP2A Cα levels in vivo suppressed proliferation and metastasis in LM8 cells. PP2A Cα expression was also higher in human osteosarcoma MG63 and SaOS-2 cells than that in primary osteoblasts and MC3T3-E1 cells, and reduction in PP2A Cα levels suppressed the cell proliferation rate and migration ability of MG63 cells. These results indicate that PP2A Cα has a critical role in the proliferation and metastasis of osteosarcoma cells; therefore, its inhibition could potentially suppress the malignancy of osteosarcoma cells.

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Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple‐negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

Jian

Kong

et al. 2022

Clinical & Translational Med

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Triple‐negative breast cancer (TNBC) is fast‐growing and highly metastatic with the poorest prognosis among the breast cancer subtypes. Inactivation of glycogen synthase kinase 3 beta (GSK3β) plays a vital role in the aggressiveness of TNBC; however, the underlying mechanism for sustained GSK3β inhibition remains largely unknown. Here, we find that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) is upregulated in TNBC and relevant to poor prognosis in patients. Overexpression of PPP1R14C facilitates cell proliferation and the aggressive phenotype of TNBC cells, whereas the depletion of PPP1R14C elicits opposite effects. Moreover, PPP1R14C is phosphorylated and activated by protein kinase C iota (PRKCI) at Thr73. p‐PPP1R14C then represses Ser/Thr protein phosphatase type 1 (PP1) to retain GSK3β phosphorylation at high levels. Furthermore, p‐PPP1R14C recruits E3 ligase, TRIM25, toward the ubiquitylation and degradation of non‐phosphorylated GSK3β. Importantly, the blockade of PPP1R14C phosphorylation inhibits xenograft tumorigenesis and lung metastasis of TNBC cells. These findings provide a novel mechanism for sustained GSK3β inactivation in TNBC and suggest that PPP1R14C might be a potential therapeutic target.

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Inhibition of protein phosphatase-1 and -2A decreases the chemosensitivity of leukemic cells to chemotherapeutic drugs

Cited by 22 publications

References 44 publications

Interplay of myosin phosphatase and protein phosphatase-2A in the regulation of endothelial nitric-oxide synthase phosphorylation and nitric oxide production

Interplay of myosin phosphatase and protein phosphatase-2A in the regulation of endothelial nitric-oxide synthase phosphorylation and nitric oxide production

Protein phosphatase 2A Cα regulates proliferation, migration, and metastasis of osteosarcoma cells

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple‐negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

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