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Synthetic Isoliquiritigenin Inhibits Human Tongue Squamous Carcinoma Cells through Its Antioxidant Mechanism.

ABSTRACT: Isoliquiritigenin (ISL), a natural antioxidant, has antitumor activity in different types of cancer cells. However the antitumor effect of ISL on human tongue squamous carcinoma cells (TSCC) is not clear. Here we aimed to investigate the effects of synthetic isoliquiritigenin (S-ISL) on TSCC and elucidate the underlying mechanisms. S-ISL was synthesized and elucidated from its nuclear magnetic resonance spectrum and examined using high performance liquid chromatography. The effects of S-ISL on TSCC cells (Tca8113) were evaluated in relation to cell proliferation, apoptosis and adhesion, migration, and invasion using sulforhodamine B assay, fluorescence microscopy technique, flow cytometry (FCM) analysis, and Boyden chamber assay. The associated regulatory mechanisms were examined using FCM and fluorescence microscopy for intracellular reactive oxygen species (ROS) generation, Gelatin zymography assay for matrix metalloproteinase (MMP) activities, and Western blot for apoptosis regulatory proteins (Bcl-2 and Bax). Our data indicated that S-ISL inhibited Tca8113 cell proliferation, adhesion, migration, and invasion while promoting the cell apoptosis. Such effects were accompanied by downregulation of Bcl-2 and upregulation of Bax, reduction of MMP-2 and MMP-9 activities, and decreased ROS production. We conclude that S-ISL is a promising agent targeting TSCC through multiple anticancer effects, regulated by its antioxidant mechanism.

SUBMITTER: Hou C

PROVIDER: S-EPMC5292127 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Synthetic Isoliquiritigenin Inhibits Human Tongue Squamous Carcinoma Cells through Its Antioxidant Mechanism.

Hou Cuilan C Li Wenguang W Li Zengyou Z Gao Jing J Chen Zhenjie Z Zhao Xiqiong X Yang Yaya Y Zhang Xiaoyu X Song Yong Y

Oxidative medicine and cellular longevity 20170122

Isoliquiritigenin (ISL), a natural antioxidant, has antitumor activity in different types of cancer cells. However the antitumor effect of ISL on human tongue squamous carcinoma cells (TSCC) is not clear. Here we aimed to investigate the effects of synthetic isoliquiritigenin (S-ISL) on TSCC and elucidate the underlying mechanisms. S-ISL was synthesized and elucidated from its nuclear magnetic resonance spectrum and examined using high performance liquid chromatography. The effects of S-ISL on T ...[more]

PMID: 28203317

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Project description:BackgroundSerine hydroxymethyltransferase 2 (SHMT2) is a vital metabolic enzyme in one carbon metabolism catalyzing the conversion of serine to glycine, which has been reported to play a crucial role in the progression of tumors. However, its function in tongue squamous cell carcinoma (TSCC) remains unclear.MethodsSHMT2 expression was analyzed using samples in online databases, and was assessed through immunohistochemistry staining of collected clinical specimens. The correlation between SHMT2 expression and the cell cycle was predicted through bioinformatic analysis, including weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA). After transfection with siRNA, CCK8 assay, Edu staining, flow cytometry, trans-well assay, and wound healing experiments were performed to verify the functional role of SHMT2 in vitro. A stable cell line with SHMT2 silencing was established to detect the oncogenic function of SHMT2 in vivo.ResultsThe expression of SHMT2 was up-regulated in TSCC tissues and cell lines compared with normal groups, and highly expressed SHMT2 significantly indicated a poorer clinical outcome for TSCC patients. Bioinformatic analysis found that high expression of SHMT2 was closely related with biologic process including cell cycle and cell cycle G1/S transition. Down regulating of SHMT2 significantly suppressed the proliferation, invasive and migrative ability of TSCC cells, and induced the prolongation of the G1 phase of the cell cycle in vitro. Furthermore, western blot showed that cell cycle-related regulators such as cyclin-dependent kinase 4 (CDK4) and cyclinD1 expression levels were decreased, while the expression levels of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 were increased after SHMT2 knockdown. Silencing SHMT2 in the HN6 cell line using short hairpin RNA also impeded tumor growth in vivo.ConclusionsOverexpression of SHMT2 in TSCC indicated low survival rates, and was associated with aggressive behaviors of TSCC. It was also found to be involved in cell cycle regulation of TSCC cells. SHMT2 may serve as a novel prognostic indicator of TSCC.

Project description:Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity.

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Synthetic Isoliquiritigenin Inhibits Human Tongue Squamous Carcinoma Cells through Its Antioxidant Mechanism.

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Synthetic Isoliquiritigenin Inhibits Human Tongue Squamous Carcinoma Cells through Its Antioxidant Mechanism.

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