The Mitogen-Activated Protein Kinase Phosphatase <i>Vaccinia</i> H1–Related Protein Inhibits Apoptosis in Prostate Cancer Cells and Is Overexpressed in Prostate Cancer

Arnoldussen, Yke Jildouw; Lorenzo, Petra I.; Pretorius, Maria E.; Wæhre, Håkon; Risberg, Bjørn; Mælandsmo, Gunhild Mari; Danielsen, Håvard E.; Saatcioglu, Fahri

doi:10.1158/0008-5472.can-08-1224

Cited by 47 publications

(50 citation statements)

References 46 publications

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“…Its expression was increased in cervix carcinoma and prostate cancer. 4 Another intriguing aspect of VHR phosphatase is that it fluctuates during the phases of cell cycle. VHR phosphatase during G1 phase is not detected due to rapid degradation.…”

mentioning

confidence: 99%

Regulation of Vaccinia H1-related (VHR) Phosphatase Activity by NSC-87877

Park¹,

Song²,

Cho

2009

Bulletin of the Korean Chemical Society

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Half maximal inhibitory constant of enzyme was determined to 7.83 ± 0.98 µM. VHR phosphatase (100 nM) was incubated with various concentrations of NSC-87877 at 37 o C for 30 min. Fluorescence emission from the product was measured with a multiwell plate reader as described in Experimental section.Based on amino-acid sequences of catalytic domains, protein tyrosine phosphatases (PTPs) can be classified into four groups 1 ; class I Cys-based PTPs, class II Cys-based PTPs, class III Cys-based PTPs, and Asp-based PTPs. Each PTP has a characteristic role in a variety of cellular processes including cellular metabolism, growth, proliferation, differentiation and also has been emerged as a therapeutic target in many diseases such as diabetes, leukemia, neurodegradation, and cancer. Class I PTPs comprise dual specificity phosphatases (DUSPs) including VHR that has diverse substrate specificities both or either on phospho-Tyr, phospho-Ser, and phospho-Thr residues. Class II PTPs that dephosphorylate only pTyr are encoded by a single gene ACP1 and related to diseases like Alzheimer's disease and asthma. Class III PTPs comprise CDC25 family proteins that regulate cell cycle by acting on Cdks. They dephosphorylate Thr-Tyr motifs of N-terminal Cdks, thus keep them from driving the cell progression.2 Asp-based PTPs encoded by only four Eya genes recently have been listed as a new family.VHR phosphatase, also called DUSP3, is a 20 kDa protein that might be one of the smallest known PTPs. VHR phosphatase can be elucidated by two particular characteristics in cellular physiology. First, VHR phosphatase shows more expression in the nucleus of cancer cells than that of normal cells. It is not due to the increase of transcription of VHR gene, but due to stabilization VHR phosphatase in cancer cell. Its expression was increased in cervix carcinoma and prostate cancer. 4 Another intriguing aspect of VHR phosphatase is that it fluctuates during the phases of cell cycle. VHR phosphatase during G1 phase is not detected due to rapid degradation. Gradually, it accumulates by means of its augmented transcription during late G1 and S phases. 5 The siRNA interference analyses also show that depletion of VHR phosphatase arrests cells at the G 1 /S, and G 2 /M phases. 5 Highly active extracellular signal regulated kinase (ERK) is a main reason of the cell cycle arrest. 6 Elevated VHR phosphatase expression results in cell cycle progression by dephosphorylating ERK. Due to its elevated protein level in cancers such as cervix carcinoma and prostate cancer and involvement in cell cycle progression, VHR phosphatase has been emerged as a therapeutic target. Therefore, it is important to identify novel inhibitor of VHR phosphatase for cancer treatment. Several VHR phosphatase inhibitors including stevastelins, 7 glucosamine-aminoehoxy triphenyltin (GATPT), 8 RK-682, 9 and 4-iA 10 have been identified so far. In search for more putative VHR phosphatase inhibitors, we investigated whether 8-hydroxy-7-[(6-sulfo-2-naphthyl)azo]-5-quinolinesulfonic acid ...

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mentioning

confidence: 99%

Regulation of Vaccinia H1-related (VHR) Phosphatase Activity by NSC-87877

Park¹,

Song²,

Cho

2009

Bulletin of the Korean Chemical Society

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“…NO overexpression has been reported in various tumors, including lung cancer, and its inhibition is regarded as an anticancer therapy (28). Cancer cells are able to evade cell cycle arrest via VHR overexpression (29). Annexins, prohibitin and different subunits of the proteasome complex have been associated with cancer invasiveness (12,13).…”

Section: Discussionmentioning

confidence: 99%

Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

et al. 2016

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Abstract. Umbelliprenin (Umb), a natural coumarin, has demonstrated anti-tumor activities, both in vitro and particularly in vivo, in several types of cancer, including lung cancer. The present study aimed to identify molecular targets of Umb using a high-throughput approach. Lung cancer cell lines, QU-DB (large-cell lung carcinoma) and A549 (adenocarcinoma), were treated with Umb. Differentially-expressed proteins were identified using two-dimensional electrophoresis coupled to mass spectrometry. In the QU-DB cells, differential expression of proteins, including downregulation of the tumorigenic protein heat shock protein 90 kDa and upregulation of the potential anti-tumor proteins Nipsnap1 and glycine-tRNA ligase (GRS), suggested that Umb is a strong anti-tumor compound. In the A549 cells, differential expression of proteins indicated possible contradictory effects of Umbregarding tumorigenesis, which included downregulation of the tumorigenic protein cyclophilin and the tumor suppressor MST, and upregulation of stathmin (tumorigenic) and calreticulin. Calreticulun, in addition to GRS in QU-DB cells, stimulates anti-tumor immune responses in vivo. To the best of our knowledge, the present study is the first to use a high-throughput approach to identify targets of Umb in cancer. These molecular targets suggested that Umb may exhibit stronger in vitro anti-tumor activity against the large-cell carcinoma model than the adenocarcinoma model. Furthermore, it has been reported that Umb exhibits higher cytotoxicity against QU-DB cells than A549 cells in vitro, and significant Umb anti-tumor activity against lung cancer in vivo, which is consistent with previously published literature. In each cell type, immune-associated molecules were upregulated, indicating that this naturally occurring compound exhibits marked anti-tumor activity in vivo. However, further studies that investigate the effect of Umb in different in vitro models of cancer are required.

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“…dusp3 expression is also down-regulated in primary non-small cell lung cancer (NSCLC) tumors [34]. A tumor suppressive function for DUSP3 in NSCLC is supported experimentally, as in both the NSCLC H1299 cell line and mouse xenographs, over-expression of dusp3 suppressed growth of cells and tumors respectively [32]. Further supporting a tumor suppressor function for DUSP3, its expression suppressed phospholipase C (PLC) -protein kinase C (PKC) signaling [36].…”

Section: Dusp3/vhrmentioning

confidence: 95%

“…Nevertheless, as a functional MAPK phosphatase, it is not surprising that DUSP3 is implicated in cancer, where it has been alternatively described as having both oncogenic [30][31][32] and tumor suppressive [33,34] properties.…”

Section: Dusp3/vhrmentioning

confidence: 99%

“…dusp3 is also over-expressed in primary prostate tumors where it may function as a pro-survival phosphatase [32]. In prostate cancer cells (LNCaP), DUSP3 functions as an inhibitor of apoptosis, where dusp3 knock-down resulted in increased JNK phosphorylation and increased apoptosis when treated with thapsigargin, an inducer of ER stress, or 12-0-tetradecanoylophorbol-13-acetate (TPA) [31].…”

Section: Dusp3/vhrmentioning

confidence: 99%

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