hSulf-1 Gene Exhibits Anticancer Efficacy through Negatively Regulating VEGFR-2 Signaling in Human Cancers

Ji, Weidan; Yang, Jiahe; Duan-ming, Wang; Cao, Lu; Tan, Weifeng; Qian, Haihua; Sun, Bin; Qian, Qijun; Yin, Zheng; Wu, Mengchao; Su, Changqing

doi:10.1371/journal.pone.0023274

Cited by 28 publications

(28 citation statements)

References 35 publications

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“…Our finding that SDC1 over-expression directly inhibits SULF1 and leads to increased HS 6-O-sulfation suggests functional consequences regarding the binding of growth factors and the regulation of intracellular signaling pathways, as previously observed for VEGFR [60], amphiregulin [61], and FGFR [62]. In our study, this is illustrated by a subtle enhancement of EGFR activity in cells over-expressing SDC1 and concomitant activation of the downstream ERK1/2 pathway.…”

Section: Discussionsupporting

confidence: 87%

Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

Heidari-Hamedani

Vivès

Seffouh

et al. 2015

Cellular Signalling

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Syndecan-1 is a proteoglycan that acts as co-receptor through its heparan sulfate (HS) chains and plays important roles in cancer. HS chains are highly variable in length and sulfation pattern. This variability is enhanced by the SULF1/2 enzymes, which remove 6-O-sulfates from HS. We used malignant mesothelioma, an aggressive tumor with poor prognosis, as a model and demonstrated that syndecan-1 over-expression down-regulates SULF1 and alters the HS biosynthetic machinery. Biochemical characterization revealed a 2.7-fold reduction in HS content upon syndecan-1 over-expression, but an overall increase in sulfation. Consistent with low SULF1 levels, trisulfated disaccharides increased 2.5-fold. ERK1/2 activity was enhanced 6-fold. Counteracting ERK activation, Akt, WNK1, and c-Jun were inhibited. The net effect of these changes manifested in G1 cell cycle arrest. Studies of pleural effusions showed that SULF1 levels are lower in pleural malignancies compared to benign conditions and inversely correlate with the amounts of syndecan-1, suggesting important roles for syndecan-1 and SULF1 in malignant mesothelioma.

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Section: Discussionsupporting

confidence: 87%

Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

Heidari-Hamedani

Vivès

Seffouh

et al. 2015

Cellular Signalling

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“…Such targets would have the potential for the creation of high-performance targeted agents for HCC therapy. Many studies have shown that significant amounts of the ligands for multiple signaling pathways can be sequestered by binding to HSPGs on the cell surface and in the extracellular matrix (Sanderson et al, 2005; Selleck, 2006; Ji et al, 2011). SULF2 is a novel member of a family of HS-degrading endosulfatases that can desulfate HS, releasing ligands bound to HSPGs and consequently modulating multiple signaling pathways (Rosen and Lemjabbar-Alaoui, 2010; Bret et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

The human sulfatase 2 inhibitor 2,4‐disulfonylphenyl‐tert‐butylnitrone (OKN‐007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling

Zheng

Gai

Han

et al. 2012

Genes Chromosomes & Cancer

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Human sulfatase 2 (SULF2) functions as an oncoprotein in hepatocellular carcinoma (HCC) development by promoting tumor growth and metastasis via enhancement of fibroblast growth factor-2/extracellular signal-regulated kinase and WNT/ β-catenin signaling. Recent results implicate that SULF2 activates the transforming growth factor beta (TGFB) and Hedgehog/GLI1 pathways in HCC. OKN-007 is a novel phenyl–sulfonyl compound that inhibits the enzymatic activity of SULF2. To investigate the antitumor effect of OKN-007 in HCC, we treated Huh7 cells, which express high levels of SULF2, with OKN-007 and found that it significantly promoted tumor cell apoptosis and inhibited cell proliferation, viability, and migration. To understand the action of OKN-007 on SULF2, we used Huh7 cells which normally express SULF2 and Hep3B cells that do not normally express SULF2. Utilizing Huh7 cells transfected with short hairpin RNA targeting SULF2 and transfection of Hep3B cells with a SULF2 plasmid to enhance SULF2 expression, we showed that the antitumor activity of OKN-007 was more pronounced in cells expressing SULF2. Furthermore, in vivo experiments verified that OKN-007 repressed tumor growth significantly. These results identify SULF2 as an important target of the antitumor effect of OKN-007. To determine the molecular mechanism of the antitumor effect of OKN-007, both TGFB1/SMAD and Hedgehog/GLI1 signaling pathway activity were measured by Western blot and SMAD- or GLI-reporter luciferase assays. We found that both signaling pathways were inhibited by OKN-007. Together, these results show that OKN-007 can suppress TGFB1/SMAD and Hedgehog/GLI1 signaling via its inhibition of SULF2 enzymatic activity. We conclude that OKN-007 or more potent derivatives may be promising agents for the treatment of HCC.

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“…It has been suggested that HSULF-1’s hydrolysis of sulfate groups from HSPGs down-regulates the receptor tyrosine kinase activity to attenuate cell growth and survival through signaling pathways regulated by FGF-2, VEGF, and HGF [19,30,31]. Based on these findings, H292 cells were forced to over-express HSULF-1 and levels of p-ERK and p-Akt, common down-stream targets of signaling pathways triggered by FGF-2, VEGF, and HGF, were analyzed.…”

Section: Discussionmentioning

confidence: 99%

HSULF-1 inhibits ERK and AKT signaling and decreases cell viability in vitro in human lung epithelial cells

2012

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BackgroundHeparan sulfate proteoglycans (HSPGs) modulate the binding and activation of signaling pathways of specific growth factors, such as fibroblast growth factor-2 (FGF-2). Human endosulfatase 1 (HSULF-1) is an enzyme that selectively removes 6-O sulfate groups from HS side chains and alter their level and pattern of sulfation and thus biological activity. It is known that HSULF-1 is expressed at low levels in some cancer cell lines and its enhanced expression can inhibit cancer cell growth or induce apoptosis, but the mechanism(s) involved has not been identified.MethodsHSULF-1 mRNA expression was assessed in five normal cells (primary human lung alveolar type 2 (hAT2) cells, adult lung fibroblasts (16Lu), fetal lung fibroblasts (HFL), human bronchial epithelial cells (HBE), and primary human lung fibroblasts (HLF)) and five lung cancer cell lines (A549, H292, H1975, H661, and H1703) using quantitative real time polymerase chain reaction (qRT-PCR). H292 and hAT2 cells over-expressing HSULF-1 were analyzed for cell viability, apoptosis, and ERK/Akt signaling, by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) assay, and Western Blot, respectively. Apoptosis pathway activation was confirmed by PCR array in hAT2, H292, and A549 cells.ResultsHSULF-1 was expressed at a significantly lower level in epithelial cancer cell lines compared to normal cells. Infection with recombinant adenovirus for HSULF-1 over-expression resulted in decreased cell viability in H292 cells, but not in normal hAT2 cells. HSULF-1 over-expression induced apoptosis in H292 cells, but not in hAT2 cells. In addition, apoptosis pathways were activated in both H292 and A549 cells, but not in hAT2 cells. HSULF-1 over-expression reduced ERK and Akt signaling activation in H292 cells, which further demonstrated its inhibitory effects on signaling related to proliferation.ConclusionsThese results indicate that HSULF-1 is expressed at lower levels in H292 lung cancer cells than in normal human alveolar cells and that its over-expression reduced cell viability in H292 cells by inducing apoptotic pathways, at least in part by inhibiting ERK/Akt signaling. We hypothesize that HSULF-1 plays important roles in cancer cells and functions to modify cell signaling, inhibit cancer proliferation, and promote cancer cell death.

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hSulf-1 Gene Exhibits Anticancer Efficacy through Negatively Regulating VEGFR-2 Signaling in Human Cancers

Cited by 28 publications

References 35 publications

Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

The human sulfatase 2 inhibitor 2,4‐disulfonylphenyl‐tert‐butylnitrone (OKN‐007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling

HSULF-1 inhibits ERK and AKT signaling and decreases cell viability in vitro in human lung epithelial cells

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