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

Zheng, Xin; Gai, Xiaowu; Han, Shaoshan; Moser, Catherine D.; Hu, Chunling; Shire, Abdirashid M.; Floyd, Robert A.; Roberts, Lewis R.

doi:10.1002/gcc.22022

Cited by 57 publications

(56 citation statements)

References 34 publications

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“…Among this short list of 13 genes were Wwp2, S100A4, Sulf2, and Inhbb, previously reported to enhance TGFb/Activin signaling ( Fig. 6A; Matsuura et al 2010;Soond and Chantry 2011;Zheng et al 2013). qRT-PCR on independently purified HF-SCs confirmed that their mRNAs were downregulated in cKO HF-SCs (Fig.…”

Section: Sox9 Is a Positive Regulator Of Genes Involved In Activin/tgmentioning

confidence: 63%

SOX9: a stem cell transcriptional regulator of secreted niche signaling factors

et al. 2014

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Hair follicles (HFs) undergo cyclical periods of growth, which are fueled by stem cells (SCs) at the base of the resting follicle. HF-SC formation occurs during HF development and requires transcription factor SOX9. Whether and how SOX9 functions in HF-SC maintenance remain unknown. By conditionally targeting Sox9 in adult HF-SCs, we show that SOX9 is essential for maintaining them. SOX9-deficient HF-SCs still transition from quiescence to proliferation and launch the subsequent hair cycle. However, once activated, bulge HF-SCs begin to differentiate into epidermal cells, which naturally lack SOX9. In addition, as HF-SC numbers dwindle, outer root sheath production is not sustained, and HF downgrowth arrests prematurely. Probing the mechanism, we used RNA sequencing (RNA-seq) to identify SOX9-dependent transcriptional changes and chromatin immunoprecipitation (ChIP) and deep sequencing (ChIP-seq) to identify SOX9-bound genes in HF-SCs. Intriguingly, a large cohort of SOX9-sensitive targets encode extracellular factors, most notably enhancers of Activin/pSMAD2 signaling. Moreover, compromising Activin signaling recapitulates SOX9-dependent defects, and Activin partially rescues them. Overall, our findings reveal roles for SOX9 in regulating adult HF-SC maintenance and suppressing epidermal differentiation in the niche. In addition, our studies expose a role for SCs in coordinating their own behavior in part through non-cell-autonomous signaling within the niche.

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Section: Sox9 Is a Positive Regulator Of Genes Involved In Activin/tgmentioning

confidence: 63%

SOX9: a stem cell transcriptional regulator of secreted niche signaling factors

et al. 2014

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“…The role of SULF2, another sulfatase enzyme, as a tumor promoter has already been established, [21][22][23] and more recently Zheng et al have shown that the TGF-b pathway can be activated by SULF2. 24 We explored the role of SULF2 in TGF-b-mediated EMT using in vitro studies and found that it had similar actions as SULF1.…”

Section: Discussionmentioning

confidence: 99%

Activation of the transforming growth factor‐β/SMAD transcriptional pathway underlies a novel tumor‐promoting role of sulfatase 1 in hepatocellular carcinoma

Dhanasekaran¹,

Nakamura²,

Hu³

et al. 2015

Hepatology

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In vitro studies have proposed a tumor suppressor role for Sulfatase1 (SULF1) in hepatocellular carcinoma (HCC), however high expression in human HCC has been associated with poor prognosis. The reason underlying this paradoxical observation remains to be explored. Using a transgenic (Tg) mouse model overexpressing Sulf1 (Sulf1-Tg) we assessed the effects of SULF1 on the diethylnitrosamine (DEN) model of liver carcinogenesis. Sulf1-Tg mice show higher incidence of large and multifocal tumors with DEN injection compared to wild type (WT) mice. Lung metastases were found in 75% of Sulf1-Tg mice but not in WT mice. Immunohistochemistry (IHC), immunoblotting and reporter assays all show a significant activation of the TGFβ/SMAD transcriptional pathway by SULF1 both in vitro and in vivo. This effect of SULF1 on TGFβ/SMAD pathway is functional; overexpression of SULF1 promotes TGFβ-induced gene expression and epithelial-mesenchymal-transition (EMT), and enhances cell migration/invasiveness. Mechanistic analyses demonstrate that inactivating mutation of the catalytic site of SULF1 impairs the above actions of SULF1 and diminishes the release of TGFβ from the cell surface. And we also show that SULF1expression decreases the interaction between TGF-β1 and its HSPG sequestration receptor TGFβR3. Finally, using gene expression from human HCCs, we show that patients with high SULF1 expression have poorer recurrence-free survival (HR 4.1 (1.9–8.3); p=0.002) compared to patients with low SULF1. We also found strong correlations of SULF1 expression with TGFβ expression and with several TGFβ-related EMT genes in human HCC. CONCLUSION In summary, our study proposes a novel role of SULF1 in HCC tumor progression through augmentation of the TGFβ pathway, thus defining SULF1 as a potential biomarker for tumor progression and a novel target for drug development for HCC.

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“…From these studies we concluded that OKN-007 has the ability to cause glioma regression in aggressive rodent tumor models (F98 and U87), as well as in moderate gliomas (C6) [8–10]. Support for the anticancer effect of OKN-007 via the transforming growth factor β1 (TGFβ1) pathway was reported by Zheng et al, where they found that OKN-007 mediates its antitumor effect in hepatocellular carcinoma cells (Huh7) via the suppression of TGFβ1/SMAD2 and Hedgehog/GLI1 signaling by inhibiting sulfatase 2 (SULF2) enzymatic activity [59]. …”

Section: Discussionmentioning

confidence: 99%

OKN-007 decreases free radical levels in a preclinical F98 rat glioma model

Souza

Smith

Atolagbe

et al. 2015

Free Radical Biology and Medicine

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Free radicals are associated with glioma tumors. Here, we report on the ability of an anticancer nitrone compound, OKN-007 [Oklahoma Nitrone 007; a disulfonyl derivative of α-phenyl-tert-butyl nitrone (PBN)] to decrease free radical levels in F98 rat gliomas using combined molecular magnetic resonance imaging (mMRI) and immunospin-trapping (IST) methodologies. Free radicals are trapped with the spin-trapping agent, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), to form DMPO macromolecule radical adducts, and then further tagged by immunospin trapping by an antibody against DMPO adducts. In this study, we combined mMRI with a biotin–Gd-DTPA–albumin-based contrast agent for signal detection with the specificity of an antibody for DMPO nitrone adducts (anti-DMPO probe), to detect in vivo free radicals in OKN-007-treated rat F98 gliomas. OKN-007 was found to significantly decrease (P < 0.05) free radical levels detected with an anti-DMPO probe in treated animals compared to untreated rats. Immunoelectron microscopy was used with gold-labeled antibiotin to detect the anti-DMPO probe within the plasma membrane of F98 tumor cells from rats administered anti-DMPO in vivo. OKN-007 was also found to decrease nuclear factor erythroid 2-related factor 2, inducible nitric oxide synthase, 3-nitrotyrosine, and malondialdehyde in ex vivo F98 glioma tissues via immunohistochemistry, as well as decrease 3-nitrotyrosine and malondialdehyde adducts in vitro in F98 cells via ELISA. The results indicate that OKN-007 effectively decreases free radicals associated with glioma tumor growth. Furthermore, this method can potentially be applied toward other types of cancers for the in vivo detection of macromolecular free radicals and the assessment of antioxidants.

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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

Cited by 57 publications

References 34 publications

SOX9: a stem cell transcriptional regulator of secreted niche signaling factors

SOX9: a stem cell transcriptional regulator of secreted niche signaling factors

Activation of the transforming growth factor‐β/SMAD transcriptional pathway underlies a novel tumor‐promoting role of sulfatase 1 in hepatocellular carcinoma

OKN-007 decreases free radical levels in a preclinical F98 rat glioma model

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