Targeting protein phosphatase PP2A for cancer therapy: development of allosteric pharmaceutical agents

2021 ◽  
Vol 135 (13) ◽  
pp. 1545-1556
Author(s):  
David L. Brautigan ◽  
Caroline Farrington ◽  
Goutham Narla
Keyword(s):  
Cell Proliferation ◽  
Protein Phosphatase ◽  
Signaling Networks ◽  
Survival Pathways ◽  
Novel Drugs ◽  
Phosphatase 2A ◽  
Therapy Development ◽  
Near Term ◽  
Small Molecule Modulators ◽  
Pharmaceutical Agents

Abstract Tumor initiation is driven by oncogenes that activate signaling networks for cell proliferation and survival involving protein phosphorylation. Protein kinases in these pathways have proven to be effective targets for pharmaceutical inhibitors that have progressed to the clinic to treat various cancers. Here, we offer a narrative about the development of small molecule modulators of the protein Ser/Thr phosphatase 2A (PP2A) to reduce the activation of cell proliferation and survival pathways. These novel drugs promote the assembly of select heterotrimeric forms of PP2A that act to limit cell proliferation. We discuss the potential for the near-term translation of this approach to the clinic for cancer and other human diseases.

scholarly journals Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 716
Author(s):  
Hisham Saafan ◽  
Ahmad Alahdab ◽  
Robin Michelet ◽  
Linus Gohlke ◽  
Janine Ziemann ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Cell Line ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Nsclc Cell ◽  
Egfr Mutations ◽  
Nsclc Cell Line ◽  
Acquired Drug Resistance ◽  
Phosphatase 2A

Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) in the HCC4006rErlo0.5 NSCLC cell line adapted to erlotinib as a model of acquired drug resistance. Constitutive CIP2A resulted in a constitutive activation of Akt signaling. The proteasome inhibitor bortezomib was able to reduce CIP2A levels, which resulted in an activation of protein phosphatase 2A and deactivation of Akt. Combination experiments with erlotinib and bortezomib revealed a lack of interaction between the two drugs. However, the effect size of bortezomib was higher in HCC4006rErlo0.5, compared to the erlotinib-sensitive HCC4006 cells, as indicated by an increase in Emax (0.911 (95%CI 0.867–0.954) vs. 0.585 (95%CI 0.568–0.622), respectively) and decrease in EC50 (52.4 µM (95%CI 46.1–58.8 µM) vs. 73.0 µM (95%CI 60.4–111 µM), respectively) in the concentration–effect model, an earlier onset of cell death induction, and a reduced colony surviving fraction (0.38 ± 0.18 vs. 0.95 ± 0.25, respectively, n = 3, p < 0.05). Therefore, modulation of CIP2A with bortezomib could be an interesting approach to overcome drug resistance to erlotinib treatment in NSCLC.

scholarly journals The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation

Cell ◽  
1993 ◽  
Vol 75 (5) ◽  
pp. 887-897 ◽  
Author(s):  
Estelle Sontag ◽  
Sergei Fedorov ◽  
Craig Kamibayashi ◽  
David Robbins ◽  
Melanie Cobb ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Map Kinase ◽  
Tumor Antigen ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Small Tumor ◽  
Phosphatase 2A ◽  
Map Kinase Pathway ◽  
Kinase Pathway

Contribution of cell proliferation possibly due to inactivation of protein phosphatase 2A to gene mutations induced by estragole

2015 ◽  
Vol 238 (2) ◽  
pp. S244
Author(s):  
Y. Ishii ◽  
K. Kuroda ◽  
S. Takasu ◽  
Y. Yokoo ◽  
T. Tsuchiya ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Gene Mutations ◽  
Phosphatase 2A

scholarly journals Serine 15 Phosphorylation of p53 Directs Its Interaction with B56γ and the Tumor Suppressor Activity of B56γ-Specific Protein Phosphatase 2A

2007 ◽  
Vol 28 (1) ◽  
pp. 448-456 ◽  
Author(s):  
Geoffrey P. Shouse ◽  
Xin Cai ◽  
Xuan Liu
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Tumor Suppressor ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Specific Protein ◽  
Suppressor Activity ◽  
Tumor Suppressor Activity ◽  
Phosphatase 2A ◽  
Tumor Suppressive Function

ABSTRACT Earlier studies have demonstrated a functional link between B56γ-specific protein phosphatase 2A (B56γ-PP2A) and p53 tumor suppressor activity. Upon DNA damage, a complex including B56γ-PP2A and p53 is formed which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21, and the inhibition of cell proliferation. Although an enhanced interaction between p53 and B56γ is observed after DNA damage, the underlying mechanism and its significance in PP2A tumor-suppressive function remain unclear. In this study, we show that the increased interaction between B56γ and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. In addition, we demonstrate that the B56γ3-induced inhibition of cell proliferation, induction of cell cycle arrest in G1, and blockage of anchorage-independent growth are also dependent on Ser15 phosphorylation of p53 and p53-B56γ interaction. Taken together, our results provide a mechanistic link between Ser15 phosphorylation-mediated p53-B56γ interaction and the modulation of p53 tumor suppressor activity by PP2A. We also show an important link between ATM activity and the tumor-suppressive function of B56γ-PP2A.

scholarly journals Dephosphorylated C/EBPα Accelerates Cell Proliferation through Sequestering Retinoblastoma Protein

2005 ◽  
Vol 25 (4) ◽  
pp. 1325-1338 ◽  
Author(s):  
Guo-Li Wang ◽  
Nikolai A. Timchenko
Keyword(s):  
Cell Proliferation ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Growth Arrest ◽  
Retinoblastoma Protein ◽  
Biological Functions ◽  
Strong Inhibitor ◽  
Enhancer Binding Protein ◽  
Phosphatase 2A ◽  
Liver Proliferation

ABSTRACT CCAAT/enhancer-binding protein alpha (C/EBPα) has been previously considered a strong inhibitor of cell proliferation which uses multiple pathways to cause growth arrest. In this paper, we describe a new function of C/EBPα, which is an acceleration of cell proliferation. This new function of C/EBPα is created in proliferating livers by protein phosphatase 2A-mediated dephosphorylation of C/EBPα at Ser193. The Ser193-dephosphorylated C/EBPα interacts with retinoblastoma protein (Rb) independently on E2Fs and sequesters Rb, leading to a reduction of E2F-Rb repressors and to acceleration of proliferation. This new function of C/EBPα requires Rb, since the dephosphorylated C/EBPα does not promote proliferation in Rb-negative cells. We also show that a balance of Rb and Ser193-dephosphorylated C/EBPα determines if the cells are growth arrested or have an increased rate of proliferation. Consistently with these findings, a significant portion of Rb is sequestered into Rb-C/EBPα complexes in proliferating livers, and E2F-Rb complexes are not detectable in these livers. Our data demonstrate a new pathway by which the phosphorylation-dependent switch of biological functions of C/EBPα promotes liver proliferation.

scholarly journals Expression of SET, an inhibitor of protein phosphatase 2A, in renal development and Wilms' tumor.

1998 ◽  
Vol 9 (10) ◽  
pp. 1873-1880
Author(s):  
S G Carlson ◽  
E Eng ◽  
E G Kim ◽  
E J Perlman ◽  
T D Copeland ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Expression ◽  
Cell Carcinoma ◽  
Protein Phosphatase ◽  
Renal Cell ◽  
Wilms Tumor ◽  
Protein Phosphatase 2A ◽  
Serum Starvation ◽  
Renal Development ◽  
Phosphatase 2A

The human gene set was originally identified as a component of the set-can fusion gene produced by a somatic translocation event in a case of acute undifferentiated leukemia. In the developing kidney, set was highly expressed in the zone of nephron morphogenesis. Recently, SET was shown to be a potent and specific inhibitor of protein phosphatase 2A, a family of major serine/threonine phosphatases involved in regulating cell proliferation and differentiation. The current study sought to define further the role of SET in the regulation of renal cell proliferation and tumorigenesis. The mRNA encoding SET was expressed at much higher levels in transformed human and rodent cell lines than in cultured renal epithelial and primary endothelial cells. Consistent with a role for SET in cell proliferation, set mRNA expression was markedly reduced in cells rendered quiescent by serum starvation, contact inhibition, or differentiation. Previous findings during renal development were extended by demonstrating that SET protein expression is also much greater in developing rat and human kidney than in fully differentiated, mature kidney. Finally, high levels of set mRNA and SET protein expression were found in Wilms' tumor, but not in renal cell carcinoma, adult polycystic kidney disease or in transitional cell carcinoma.

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