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Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer.

ABSTRACT: We utilized three tiers of screening to identify novel therapeutic agents for pancreatic cancers. First, we analyzed 14 pancreatic cancer cell lines against a panel of 66 small-molecule kinase inhibitors and dasatinib was the most potent. Second, we performed RNA expression analysis on 3 dasatinib-resistant and 3 dasatinib-sensitive pancreatic cancer cell lines to profile their gene expression. Third, gene profiling data was integrated with the Connectivity Map database to search for potential drugs. Thioridazine was one of the top ranking small molecules with highly negative enrichment. Thioridazine and its family members of phenothiazine including penfluridol caused pancreatic cancer cell death and affected protein expression levels of molecules involved in cell cycle regulation, apoptosis, and multiple kinase activities. This family of drugs causes activation of protein phosphatase 2 (PP2A). The drug FTY-720 (activator of PP2A) induced apoptosis of pancreatic cancer cells. Silencing catalytic unit of PP2A rendered pancreatic cancer cells resistant to penfluridol. Our observations suggest potential therapeutic use of penfluridol or similar agent associated with activation of PP2A in pancreatic cancers.

SUBMITTER: Chien W

PROVIDER: S-EPMC4387089 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A B56gamma mutation in lung cancer disrupts the p53-dependent tumor-suppressor function of protein phosphatase 2A.

Project description:Earlier studies have shown both p53-dependent and -independent tumor-suppressive functions of B56gamma-specific protein phosphatase 2A (B56gamma-PP2A). In the absence of p53, B56gamma-PP2A can inhibit cell proliferation and cell transformation by an unknown mechanism. In the presence of p53, on DNA damage, a complex including B56gamma-PP2A and p53 is formed, which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21 and inhibition of cell proliferation. In spite of its significance in inhibition of cell proliferation, no B56gamma mutations have been linked to human cancer to date. In this study, we first differentiate between the p53-dependent and -independent functions of B56gamma-PP2A by identifying a domain of the B56gamma protein required for interaction with p53. Within this region, we identify a B56gamma mutation, F395C, in lung cancer that disrupts the B56gamma-p53 interaction. More importantly, we show that F395C is unable to promote p53 Thr55 dephosphorylation, transcriptional activation of p21 and the p53-dependent tumor-suppressive function of PP2A. This finding provides a mechanistic basis for the p53-dependent and -independent functions of B56gamma-PP2A and establishes a critical link between B56gamma-PP2A p53-dependent tumor-suppressive function and tumorigenesis.

| S-EPMC2900437 | biostudies-literature

The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene

Project description:Men with melanoma have a significantly worse prognosis than women, and the biological underpinnings of this difference are unknown. The current study demonstrates that loss of the inactivated X chromosome in melanomas arising in females is strongly associated with poor distant metastasis free survival. High expression of the gonosomal PPP2R3B gene, a gene that escapes inactivation, is independently correlated with survival. PPP2R3B downregulates melanoma growth by negatively interfering with DNA replication and cell cycle progression through its role in stabilizing CDC6/CDT1 interaction during the replication origins firing and as such behaves functionally as a tumor suppressor gene. Fourty-nine fresh frozen primary melanoma samples were profiled by CGH array using sex-matched commercial DNA as reference.

2016-08-01 | E-GEOD-66839 | biostudies-arrayexpress

The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene

2016-08-01 | GSE66839 | GEO

Potential Protein Phosphatase 2A Agents from Traditional Chinese Medicine against Cancer.

Project description:Protein phosphatase 2A (PP2A) is an important phosphatase which regulates various cellular processes, such as protein synthesis, cell growth, cellular signaling, apoptosis, metabolism, and stress responses. It is a holoenzyme composed of the structural A and catalytic C subunits and a regulatory B subunit. As an environmental toxin, okadaic acid, is a tumor promoter and binds to PP2A catalytic C subunit and the cancer-associated mutations in PP2A structural A subunit in human tumor tissue; PP2A may have tumor-suppressing function. It is a potential drug target in the treatment of cancer. In this study, we screen the TCM compounds in TCM Database@Taiwan to investigate the potent lead compounds as PP2A agent. The results of docking simulation are optimized under dynamic conditions by MD simulations after virtual screening to validate the stability of H-bonds between PP2A- α protein and each ligand. The top TCM candidates, trichosanatine and squamosamide, have potential binding affinities and interactions with key residues Arg89 and Arg214 in the docking simulation. In addition, these interactions were stable under dynamic conditions. Hence, we propose the TCM compounds, trichosanatine and squamosamide, as potential candidates as lead compounds for further study in drug development process with the PP2A- α protein.

| S-EPMC4020536 | biostudies-literature

Protein phosphatase 2A activation promotes heart transplant acceptance in mice

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2023-07-20 | GSE236206 | GEO

<i>LITAF</i> is a potential tumor suppressor in pancreatic cancer.

Project description:Early diagnosis of pancreatic cancer, one of the most deadly cancers with low survival rates, is difficult, and effective biomarkers are urgently needed. Lipopolysaccharide-induced tumor necrosis factor-α factor (LITAF) has been recently proposed as a potential tumor suppressor gene in several types of cancer. Here, we analyzed the biological function of LITAF in pancreatic cancer. The LITAF gene and protein levels were decreased in pancreatic tumor tissues compared with their paired adjacent non-cancerous tissues. In addition, patients with the lower LITAF protein expression had lower disease-free survival rates. The decreased LITAF expression correlated with LITAF promoter hypermethylation in pancreatic cancer cells and tissues. Moreover, promoter demethylation dose-dependently increased the LITAF transcription. Importantly, LITAF demethylation suppressed proliferation and cell cycle progression, and enhanced apoptosis of pancreatic cancer cells. Together, our results indicate that LITAF functions as a tumor suppressor gene in pancreatic cancer cells, and might serve as a novel biomarker for early diagnosis of pancreatic cancer.

| S-EPMC5790452 | biostudies-literature

PR55? Subunit of Protein Phosphatase 2A Supports the Tumorigenic and Metastatic Potential of Pancreatic Cancer Cells by Sustaining Hyperactive Oncogenic Signaling.

Project description:The protein phosphatase 2 (PP2A) holoenzyme consists of a catalytic subunit, a scaffold subunit, and a regulatory subunit. Based on loss-of-function analysis using PP2A catalytic inhibitors or inhibition via tumor viral antigens, limited studies suggest that PP2A is a putative tumor suppressor. However, PP2A has also been shown to facilitate the activation of oncogenic signaling pathways when associated with specific regulatory subunits. In this study, we investigated the possible oncogenic role of PP2A in pancreatic cancer. We found a striking increase in the expression of PR55? (PPP2R2A), a PP2A regulatory subunit, in pancreatic cancer cells compared with normal pancreatic epithelial cells. Consistently, PR55? expression was markedly elevated in pancreatic ductal adenocarcinoma tissues compared with adjacent normal pancreatic tissues (P < 0.0001) and correlated with poor survival of pancreatic cancer patients (P < 0.0003). RNAi-mediated depletion of PR55? in pancreatic cancer cell lines resulted in diminished phosphorylation of both AKT and ERK1/2 (MAPK3/1) and decreased protein levels of ?-catenin (CTNNB1). Accordingly, pancreatic cancer cells with reduced PR55? expression exhibited significantly impaired properties of transformation, including attenuated cell growth, clonogenicity, mobility, and anchorage-independent growth. Moreover, orthotopic implantation of PR55?-depleted pancreatic cancer cells into nude mice resulted in markedly reduced tumorigenicity (P < 0.001) and distant metastases. Together, these results suggest that PR55? promotes pancreatic cancer development by sustaining hyperactivity of multiple oncogenic signaling pathways, including AKT, ERK, and Wnt. These studies also provide a basis for exploring PR55? as a diagnostic or therapeutic target in pancreatic cancer. Cancer Res; 76(8); 2243-53. ©2016 AACR.

| S-EPMC4873354 | biostudies-literature

Impaired expression of protein phosphatase 2A subunits enhances metastatic potential of human prostate cancer cells through activation of AKT pathway.

Project description:BackgroundProtein phosphatase 2A (PP2A) is a dephosphorylating enzyme, loss of which can contribute to prostate cancer (PCa) pathogenesis. The aim of this study was to analyse the transcriptional and translational expression patterns of individual subunits of the PP2A holoenzyme during PCa progression.MethodsImmunohistochemistry (IHC), western blot, and real-time PCR was performed on androgen-dependent (AD) and androgen-independent (AI) PCa cells, and benign and malignant prostate tissues for all the three PP2A (scaffold, regulatory, and catalytic) subunits. Mechanistic and functional studies were performed using various biochemical and cellular techniques.ResultsThrough immunohistochemical analysis we observed significantly reduced levels of PP2A-A and -B'? subunits (P<0.001 and P=0.0002) in PCa specimens compared with benign prostate. Contemporarily, there was no significant difference in PP2A-C subunit expression between benign and malignant tissues. Similar to the expression pattern observed in tissues, the endogenous levels of PP2A-A and B'? subunits were abrogated from the low metastatic to high metastatic and AD to AI cell line models, without any change in the catalytic subunit expression. Furthermore, using in vitro studies we demonstrated that PP2A-A? scaffold subunit has a role in dampening AKT, ?-catenin, and FAK (focal adhesion kinase) signalling.ConclusionWe conclude that loss of expression of scaffold and regulatory subunits of PP2A is responsible for its altered function during PCa pathogenesis.

| S-EPMC3694226 | biostudies-literature

Cancerous inhibitor of Protein Phosphatase 2A promotes B-cell activation in vitro

Project description:The generation of optimal immune response requires combined activation of both T- and B-cells. Here, we demonstrate that the cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel factor that governs activation of both T- and B-cells in vivo. Upon ovalbumin challenge, CIP2A-deficient (CIP2AHOZ) mice show impaired immune response. Furthermore, CIP2AHOZ mice had impaired clearance of Listeria Monocytogenesis (L.m.) infection, combined with decreased numbers of CD8+ T-cells and IFN-γ secretion. In an ovalbumin model of allergic asthma, CIP2AHOZ B-cells were impaired in IgE and IgG secretion, despite of normal Th2 differentiation and unaffected numbers of inflammatory cells or cytokines in bronchoalveolar lavage. Importantly, the cell-autonomous effect of CIP2A deficiency for both T- and B-cell activation was confirmed by in vitro assays. During the T-cell activation CIP2A, was shown to promote expression of ETS-1, whereas in B-cells CIP2A loss resulted in inhibition of MYC-mediated gene expression. Together these results identify CIP2A as a novel cell-autonomous regulator governing both T- and B-cell activation in vivo. They also identify CIP2AHOZ as a novel murine model for investigation of impaired immune response and allergic asthma.

2015-12-01 | GSE63391 | GEO

Serine 15 phosphorylation of p53 directs its interaction with B56gamma and the tumor suppressor activity of B56gamma-specific protein phosphatase 2A.

Project description:Earlier studies have demonstrated a functional link between B56gamma-specific protein phosphatase 2A (B56gamma-PP2A) and p53 tumor suppressor activity. Upon DNA damage, a complex including B56gamma-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 B56gamma 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 B56gamma and p53 after DNA damage requires ATM-dependent phosphorylation of p53 at Ser15. In addition, we demonstrate that the B56gamma3-induced inhibition of cell proliferation, induction of cell cycle arrest in G(1), and blockage of anchorage-independent growth are also dependent on Ser15 phosphorylation of p53 and p53-B56gamma interaction. Taken together, our results provide a mechanistic link between Ser15 phosphorylation-mediated p53-B56gamma 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 B56gamma-PP2A.

| S-EPMC2223295 | biostudies-literature

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