PTP4A3

Over 34 000 patients are diagnosed yearly with multiple myeloma (MM), which remains a fatal malignancy. Expression of the phosphatase PRL-3 is associated with poor prognosis in MM patients, and Vandsemb et al. have demonstrated that PRL-3 contributes to enhanced MM cell fitness through activation of a glycolysis-associated feedback loop. PRL-3 resulted in increased expression of signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2) and increased glycolysis. Increased glucose metabolism in turn activated STAT1/2 and interferon 1-related genes...

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5-20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays...

Expression of the phosphatase of regenerating liver-3 (PRL-3) is known to promote tumor growth in gastrointestinal adenocarcinomas, and the incidence of tumor formation upon inflammatory events correlates with PRL-3 levels in mouse models. These carcinomas and their onset are associated with the impairment of intestinal cell homeostasis, which is regulated by a balanced number of Paneth cells and Lgr5 expressing intestinal stem cells (Lgr5+ ISCs). Nevertheless, the consequences of PRL-3 overexpression on cellular homeostasis and ISC fitness in vivo are unexplored...

Multiple myeloma (MM) is an incurable hematologic malignancy resulting from the clonal expansion of plasma cells. MM cells are interacting with components of the bone marrow microenvironment such as cytokines to survive and proliferate. Phosphatase of regenerating liver (PRL)-3, a cytokine-induced oncogenic phosphatase, is highly expressed in myeloma patients and is a mediator of metabolic reprogramming of cancer cells. To find novel pathways and genes regulated by PRL-3, we characterized the global transcriptional response to PRL-3 overexpression in two MM cell lines...

We developed JMS-053, a potent inhibitor of the dual specificity phosphatase PTP4A3 that is potentially suitable for cancer therapy. Due to the emerging role of the unfolded protein response (UPR) in cancer pathology, we sought to identify derivatives that combine PTP4A3 inhibition with induction of endoplasmatic reticulum (ER) stress, with the goal to generate more potent anticancer agents. We have now generated bifunctional analogs that link the JMS-053 pharmacophore to an adamantyl moiety and act in concert with the phosphatase inhibitor to induce ER stress and cell death...

Protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) is highly expressed in a variety of cancers, where it promotes tumor cell migration and metastasis leading to poor prognosis. Despite its clinical significance, small molecule inhibitors of PRL-3 are lacking. Here, we screened 1443 FDA-approved drugs for their ability to inhibit the activity of the PRL phosphatase family. We identified five specific inhibitors for PRL-3 as well as one selective inhibitor of PRL-2. Additionally, we found nine drugs that broadly and significantly suppressed PRL activity...

NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass spectrometry, we demonstrate a novel role of NSD2 in chromatin remodeling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was noncanonical and independent of the SWI/SNF complex. RNA sequencing identified PTP4A3 as a downstream target of NSD2 and mapped NSD2-SMARCA2 complex on PTP4A3 promoter. This led to a focal increase in the permissive H3K36me2 mark and transcriptional activation of PTP4A3...

Cancer cells often depend on microenvironment signals from molecules such as cytokines for proliferation and metabolic adaptations. PRL-3, a cytokine-induced oncogenic phosphatase, is highly expressed in multiple myeloma cells and associated with poor outcome in this cancer. We studied whether PRL-3 influences metabolism. Cells transduced to express PRL-3 had higher aerobic glycolytic rate, oxidative phosphorylation, and ATP production than the control cells. PRL-3 promoted glucose uptake and lactate excretion, enhanced the levels of proteins regulating glycolysis and enzymes in the serine/glycine synthesis pathway, a side branch of glycolysis...

Many cell signaling pathways are activated or deactivated by protein tyrosine phosphorylation and dephosphorylation, catalyzed by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), respectively. Even though PTPs are as important as PTKs in this process, their role has been neglected for a long time. Multiple myeloma (MM) is a cancer of plasma cells, which is characterized by production of monoclonal immunoglobulin, anemia and destruction of bone. MM is still incurable with high relapse frequency after treatment...

BACKGROUND: Renal cell carcinoma (RCC) is a common urological cancer, and its risk correlates with environmental factors such as obesity, smoking and hypertension. Microarray technology enables analysis of the expression pattern of the whole phosphatome, members of which are involved in many cellular pathways and may act as either tumour suppressors or oncogenes in cancers. MATERIALS AND METHODS: We analysed data for the expression level of 87 out of 107 known protein phosphatase genes included in the Hugo Gene Nomenclature Committee Website for 72 RCC tissues and paired healthy tissues obtained from the GEO Database...

Protein tyrosine phosphatase (PTP) 4A3 is frequently overexpressed in human solid tumors and hematologic malignancies and is associated with tumor cell invasion, metastasis, and a poor patient prognosis. Several potent, selective, and allosteric small molecule inhibitors of PTP4A3 were recently identified. A lead compound in the series, JMS-053 (7-imino-2-phenylthieno[3,2- c ]pyridine-4,6(5 H ,7 H )-dione), has a long plasma half-life (∼ 24 hours) in mice, suggesting possible binding to serum components. We confirmed by isothermal titration calorimetry that JMS-053 binds to human serum albumin...

BACKGROUND/AIM: Deregulated activation of signaling through the RAS/RAF/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/RAF/MEK/ERK) and signal transducer and activator of transcription (STAT) pathways is involved in numerous hematological malignancies, making it an attractive therapeutic target. This study aimed to assess the effect of the combination of ERK2 inhibitor VX-11e and STAT3 inhibitor STA-21 on acute lymphoblastic leukemia cell lines REH and MOLT-4...

BACKGROUND: PTP4A3 is a subclass of a protein tyrosine phosphatase super family and is expressed in a range of epithelial neoplasms. We evaluated PTP4A3 expression and its association with clinicopathological parameters in different types of functioning pituitary adenomas. METHODS: A total of 34 functioning pituitary adenomas samples were evaluated in this observational study. PTP4A3 expression was examined by immunohistochemical staining, and, possible correlations between PTP4A3 and some clinicopathological variables were investigated...

Endosulfan is a persistent organochlorine pesticide that bioaccumulates in human body through the food chain and thus represents a potential risk to public health. Despite epidemiological studies, the molecular mechanisms underlying the carcinogenic effects of endosulfan in the prostate remain poorly understood. In this study, we investigated the effect of endosulfan on epithelial-mesenchymal transition (EMT) in human prostate cancer PC3 and DU145 cells. Endosulfan induced alterations of EMT biomarkers, reflecting repression of E-cadherin expression and induction of fibronectin, snail2, ZEB2, Twist1 and Vimentin...

Aging of the circulatory system correlates with the pathogenesis of a large spectrum of diseases. However, it is largely unknown which factors drive the age-dependent or pathological decline of the vasculature and how vascular defects relate to tissue aging. The goal of the study is to design a multianalytical approach to identify how the cellular microenvironment (i.e., fibroblasts) and serum from healthy donors of different ages or Alzheimer disease (AD) patients can modulate the functionality of organ-specific vascular endothelial cells (VECs)...

In the present study, we aimed to identify some genes closely related to AML prognosis and investigate their potential roles. RNA-seq data of AML samples were accessed from the TCGA database and then analyzed in the Wilcox test. AML survival-related genes were selected and an 8-gene signature-based risk score model was in turn constructed (including TET3, S100A4, BATF, CLEC11A, PTP4A3, SPATS2L, SDHA, and ATOX1 8 feature genes) using the multivariate Cox regression analysis. Kaplan-Meier analysis was performed on the 8 genes in the training set ( p  = 2...

Several types of genetic alterations occurring at numerous loci have been described in attention deficit hyperactivity disorder (ADHD). However, the role of rare single nucleotide variants (SNVs) remains under investigated. Here, we sought to identify rare SNVs with predicted deleterious effect that may contribute to ADHD risk. We chose to study ADHD families (including multi-incident) from a population with a high rate of consanguinity in which genetic risk factors tend to accumulate and therefore increasing the chance of detecting risk alleles...

Endosulfan is a persistent organic pollutant and can cause endothelial dysfunction, closely related to cardiovascular diseases. Endothelial cell migration plays a critical role in atherosclerosis and angiogenesis. This study was aimed to investigate the effect of environmentally relevant doses of endosulfan and underlying molecular mechanism on endothelial cell migration. Human umbilical vein endothelial cells (HUVECs) were treated with DMSO (control) or endosulfan (0.1, 1, 10 and 20 μM) in the presence or absence of inhibitors...

Benzene, a commonly used chemical, has been confirmed to specifically affect the hematopoietic system as well as overall human health. PTP4A3 is overexpressed in leukemia cells and is related to cell proliferation. We previously found that HIF-1alpha was involved in benzene toxicity and PTP4A3 may be the target gene of HIF-1alpha via ChIP-seq. The aim of this study is to confirm the relationship between HIF-1alpha and PTP4A3 in benzene toxicity, as well as the function of PTP4A3 on cell toxicity induced by 1,4-benzoquinone (1,4-BQ)...

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer. There are no immunotherapies and few molecularly targeted therapeutics available for treatment of this malignancy. The identification and characterization of genes and pathways that drive T-ALL progression are critical for the development of new therapies for T-ALL. Here, we determined that the protein tyrosine phosphatase 4A3 (PTP4A3 or PRL-3) plays a critical role in T-ALL initiation and progression by promoting leukemia cell migration...