Targeting phosphatases of regenerating liver (PRLs) in cancer

Min, Wei; Korotkov, Konstantin V.; Blackburn, Jessica S.

doi:10.1016/j.pharmthera.2018.05.014

Cited by 39 publications

(50 citation statements)

References 87 publications

(143 reference statements)

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“…While we hypothesize the lack of T-ALL engraftment associated with PRL-3 knock-down may be attributed to a decreased ability of the leukemia cells to migrate and home to the bone marrow or thymus niche after xenograft, this needs to be confirmed experimentally. Given PRL-3 is established as enhancing viability and preventing apoptosis in other cancers 44 , PRL-3 might be playing additional roles in vivo that contribute to fitness of the T-ALL cells.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Protein tyrosine phosphatase 4 A (PTP4A) is a member of the phosphatase of regenerating liver (PRL) family, and PRLs are oncogenic across many human cancers 38 . Here, we discussed the results of AXL activation; however, PTP4A in human cancers should be considered in future studies.…”

Section: Discussionmentioning

confidence: 99%

(−)-Epigallocatechin gallate inhibits stemness and tumourigenicity stimulated by AXL receptor tyrosine kinase in human lung cancer cells

Namiki

Wongsirisin

Yokoyama

et al. 2020

Sci Rep

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Cancer stem cells (H1299-sdCSCs) were obtained from tumour spheres of H1299 human lung cancer cells. We studied low stiffness, a unique biophysical property of cancer cells, in H1299-sdCSCs and parental H1299. Atomic force microscopy revealed an average Young's modulus value of 1.52 kPa for H1299-sdCSCs, which showed low stiffness compared with that of H1299 cells, with a Young's modulus value of 2.24 kPa. (−)-Epigallocatechin gallate (EGCG) reversed the average Young's modulus value of H1299-sdCSCs to that of H1299 cells. EGCG treatment inhibited tumour sphere formation and ALDH1A1 and SNAI2 (Slug) expression. AXL receptor tyrosine kinase is highly expressed in H1299-sdcScs and AXL knockdown with siAXLs significantly reduced tumour sphere formation and ALDH1A1 and SNAI2 (Slug) expression. An AXL-high population of H1299-sdCSCs was similarly reduced by treatment with EGCG and siAXLs. Transplantation of an AXL-high clone isolated from H1299 cells into SCID/Beige mice induced faster development of bigger tumour than bulk H1299 cells, whereas transplantation of the AXL-low clone yielded no tumours. Oral administration of EGCG and green tea extract (GTE) inhibited tumour growth in mice and reduced p-AXL, ALDH1A1, and SLUG in tumours. Thus, EGCG inhibits the stemness and tumourigenicity of human lung cancer cells by inhibiting AXL. Green tea and (−)-epigallocatechin gallate (EGCG), the main constituent of green tea catechins, prevent cancer in humans, as demonstrated in phase II clinical trials, which showed that EGCG prevented colorectal adenoma recurrence and prostate cancer development from high-grade prostate intraepithelial neoplasia 1-4. Numerous investigators have reported therapeutic effects in various human cancer cell lines by combining EGCG and other green tea catechins with anticancer compounds, including anticancer drugs, nonsteroidal anti-inflammatory drugs, and phytochemicals 5,6. Because EGCG inhibits the expression of stemness marker genes and epithelialmesenchymal transition (EMT)-related genes in human cancer stem cells (CSCs) of the breast, lung, prostate and liver, CSCs are targets of EGCG for cancer prevention and therapy 7. Using atomic force microscopy (AFM), Gimzewski's laboratory first reported that metastatic cancer cells obtained from the pleural fluids of various cancer patients showed lower average Young's modulus values, indicating lower cell stiffness, than those of normal mesothelial cells from pleural effusion 8. Furthermore, they showed that treatment with green tea extract (GTE) increased the average Young's modulus values for metastatic cancer cells (i.e., reversed the values to those of normal cell stiffness levels) 9. Our previous study revealed that EGCG increased the stiffness of H1299 and Lu99 human non-small cell lung cancer (NSCLC) cells, inhibited the high expression of EMT-related proteins, such as vimentin and SLUG, and reduced cell motility 10. To investigate the inhibitory effects of EGCG on the biophysical properties of CSCs, we enriched CSCs from the tumour spheres of

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“…Although the oncogenic role of PTP4A3 has been reported in solid tumors, its functional role in T-ALL progression has not been demonstrated [10]. The high expression of PTP4A3 in T-ALL patient samples and its role in promoting migration in T-ALL cell lines suggests it may play an oncogenic role in T-ALL.…”

Section: Ptp4a3 Increases Circulation Of T-all Cells In a Zebrafish Mmentioning

confidence: 99%

“…Protein Tyrosine Phosphatase 4A3 (PTP4A3), also known as PRL-3, is an oncogenic phosphatase that has received significant attention as a potential therapeutic target in a variety of cancers over the last decade [10]. PTP4A3 has been extensively reported as a biomarker of tumor progression and metastasis; for example, PTP4A3 expression is documented to be significantly elevated in tumor tissues compared with healthy tissues, and in advanced metastatic versus early stage tumors across a variety of solid tumor types, including breast [11], colon [12,13], gastric [14], brain [15], and prostate [16] as well as in Acute Myelogenous Leukemia (AML) [15,[17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Protein Tyrosine Phosphatase 4A3 (PTP4A3) modulates Src signaling in T-cell Acute Lymphoblastic Leukemia to promote leukemia migration and progression

Min

Haney

Blackburn

2019

Preprint

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Highlights• A subset of T-cell Acute Lymphoblastic Leukemia (T-ALL) highly express the phosphatase PTP4A3• PTP4A3 expression promotes leukemia development in zebrafish T-ALL models• Loss of PTP4A3 prevents T-ALL engraftment in mouse xenograft models • Knock-down or small molecule inhibition of PTP4A3 prevents T-ALL migration in part via modulation of SRC signaling.Abstract T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive blood cancer, and currently, there are no immunotherapies or molecularly targeted therapeutics available for treatment of this malignancy. The identification and characterization of genes and pathways that drive T-ALL progression is critical for development of new therapies for T-ALL. Here, we determined that Protein Tyrosine Phosphatase 4A3 (PTP4A3) plays a critical role in disease initiation and progression by promoting cell migration in T-ALL. PTP4A3 expression was upregulated in patient T-ALL samples at both the mRNA and protein levels compared to normal lymphocytes. Inhibition of PTP4A3 function with a small molecule inhibitor and knock-down of PTP4A3 expression using short-hairpin RNA (shRNA) in human T-ALL cells significantly impeded T-ALL cell migration capacity in vitro and reduced their ability to engraft and proliferate in vivo in xenograft mouse models. Additionally, PTP4A3 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) revealed that manipulation of PTP4A3 expression levels in T-ALL cells directly affected the SRC signaling pathway,which plays a well-characterized role in migratory behavior of several cell types. Taken together, our study revealed that PTP4A3 is a key regulator of T-ALL migration via SRC signaling, and suggests that PTP4A3 plays an important role as an oncogenic driver in T-ALL.

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Targeting phosphatases of regenerating liver (PRLs) in cancer

Cited by 39 publications

References 87 publications

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

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

(−)-Epigallocatechin gallate inhibits stemness and tumourigenicity stimulated by AXL receptor tyrosine kinase in human lung cancer cells

Protein Tyrosine Phosphatase 4A3 (PTP4A3) modulates Src signaling in T-cell Acute Lymphoblastic Leukemia to promote leukemia migration and progression

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