Phosphatase of regenerating liver 3 (PRL-3) is overexpressed in human prostate cancer tissue and promotes growth and migration

Vandsemb, Esten N.; Bertilsson, Helena; Abdollahi, Pegah; Størkersen, Øystein; Våtsveen, Thea Kristin; Rye, Morten; Rø, Torstein Baade; Børset, Magne; Slørdahl, Tobias S.

doi:10.1186/s12967-016-0830-z

Cited by 28 publications

(32 citation statements)

References 39 publications

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“…Similar to the cancers described above, upregulated PRL‐3 in tumors has been found in cervix , kidney , glioma , bladder , melanoma , lung , and prostate cancers. As for PRL‐1 and ‐2, using microarray analysis, mRNA levels were shown to be upregulated in pancreatic tumor samples compared with those of normal pancreas .…”

Section: Prl Expression In Tumors and Metastases: Emerging Biomarker supporting

confidence: 70%

“…However, one study indicated that PRL-3 expression has no clinical role in ovarian carcinoma, whereas surprisingly PRL-1 and PRL-2 expression is associated with longer survival [113]. Similar to the cancers described above, upregulated PRL-3 in tumors has been found in cervix [114], kidney [115,116], glioma [117,118], bladder [119], melanoma [120], lung [121], and prostate [122][123][124] cancers. As for PRL-1 and -2, using microarray analysis, mRNA levels were shown to be upregulated in pancreatic tumor samples compared with those of normal pancreas [125].…”

Section: Prl Expression In Tumors and Metastases: Emerging Biomarker mentioning

confidence: 85%

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Physiological and oncogenic roles of the PRL phosphatases

et al. 2018

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The human Phosphatase of Regenerative Liver (PRL) family comprises three members (PRL-1, -2, -3; gene name PTP4A1, PTP4A2, PTP4A3) that are highly expressed in a majority of cancers. This review summarizes our current understanding of PRL biology, including an overview of their evolutionary relationships and the regulatory mechanisms controlling their expression. We provide an updated view on our current knowledge on the PRL functions in solid tumors, hematological cancer, and normal physiology, particularly emphasizing on the use of in vivo mouse models. We also highlight a novel relationship positioning PRL as a central node controlling magnesium homeostasis through an association with the CNNM proteins, which are involved in magnesium transport.

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Section: Prl Expression In Tumors and Metastases: Emerging Biomarker supporting

confidence: 70%

Section: Prl Expression In Tumors and Metastases: Emerging Biomarker mentioning

confidence: 85%

Physiological and oncogenic roles of the PRL phosphatases

et al. 2018

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“…Protein tyrosine phosphatase 4A3 (PTP4A3), also known as phosphatase of regenerating liver 3 (PRL-3), is an oncogenic phosphatase that has received significant attention as a potential therapeutic target in a variety of cancers 7,8,10 . PRL-3 is highly expressed in~80% of 151 human tumor tissue samples across 11 tumor types, including liver, lung, colon, breast, stomach, thyroid, pancreas, kidney, bladder, and prostate cancer 10 , and PRL-3 has been extensively reported as a biomarker of tumor progression and metastasis in breast 11 , colon 12,13 , gastric 14 , brain 15 , and prostate 16 cancers. Elevated PRL-3 correlates with reduced survival in patients with breast 17 , gastric 14 , ovarian 18 , and liver 19 cancers and in acute myelogenous leukemia (AML) 20,21 .…”

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confidence: 99%

Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) drives migration and progression of T-cell acute lymphoblastic leukemia in vitro and in vivo

et al. 2020

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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. PRL-3 is highly expressed in patient T-ALL samples at both the mRNA and protein levels compared to normal lymphocytes. Knock-down of PRL-3 expression using short-hairpin RNA (shRNA) in human T-ALL cell lines significantly impeded T-ALL cell migration capacity in vitro and reduced their ability to engraft and proliferate in vivo in xenograft mouse models. Additionally, PRL-3 overexpression in a Myc-induced zebrafish T-ALL model significantly accelerated disease onset and shortened the time needed for cells to enter blood circulation. Reverse-phase protein array (RPPA) and gene set enrichment analysis (GSEA) revealed that the SRC signaling pathway is affected by PRL-3. Immunoblot analyses validated that manipulation of PRL-3 expression in T-ALL cells affected the SRC signaling pathway, which is directly involved in cell migration, although Src was not a direct substrate of PRL-3. More importantly, T-ALL cell growth and migration were inhibited by small molecule inhibition of PRL-3, suggesting that PRL-3 has potential as a therapeutic target in T-ALL. Taken together, our study identifies PRL-3 as an oncogenic driver in T-ALL both in vitro and in vivo and provides a strong rationale for targeted therapies that interfere with PRL-3 function. Oncogenesis 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,;

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“…While their normal cellular functions are largely unknown, the PRL family has been repeatedly shown to be involved in cancer progression. In particular, PRL-3 is a well-defined biomarker of metastasis in multiple cancer types, including melanoma, colorectal, and ovarian cancers, where PRL-3 expression is significantly higher in metastatic lesions compared to the primary tumor site [6][7][8][9][10][11][12][13][14] . In a comprehensive study of 151 patient samples across eleven common human tumors types, PRL-3 protein expression was upregulated in 80.6% of tumor samples compared to matched normal tissue 15 .…”

Section: Introductionmentioning

confidence: 99%

A screen of FDA-approved drugs identifies inhibitors of Protein Tyrosine Phosphatase 4A3 (PTP4A3 or PRL-3)

Rivas

Cerna

Smith

et al. 2020

Preprint

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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, there are currently no viable options to target PRL-3 in vivo. Here, we screened 1,443 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. Two of these broad PRL inhibitors, Salirasib and Candesartan blocked PRL-3-induced migration in human embryonic kidney (HEK) cells with no negative impact on cell viability. Both drugs prevented migration of PRL-3 expressing human colorectal cancer cells to a similar degree as the research-grade PRL inhibitor, Thienopyridone, and are selective towards PRLs over other phosphatases. In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CX5R motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.

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Phosphatase of regenerating liver 3 (PRL-3) is overexpressed in human prostate cancer tissue and promotes growth and migration

Cited by 28 publications

References 39 publications

Physiological and oncogenic roles of the PRL phosphatases

Physiological and oncogenic roles of the PRL phosphatases

Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) drives migration and progression of T-cell acute lymphoblastic leukemia in vitro and in vivo

A screen of FDA-approved drugs identifies inhibitors of Protein Tyrosine Phosphatase 4A3 (PTP4A3 or PRL-3)

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