Concerted Suppression of STAT3 and GSK3β Is Involved in Growth Inhibition of Non-Small Cell Lung Cancer by Xanthatin

Li, Tao; Fan, Fangtian; Liu, Yuping; Li, Weidong; Zhang, Lei; Ruan, Junshan; Shen, Cunsi; Sheng, Xiaobo; Zhu, Zhaohui; Wang, Aiyun; Chen, Wenxing; Huang, Shile; Lu, Yin

doi:10.1371/journal.pone.0081945

Cited by 22 publications

(12 citation statements)

References 42 publications

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“…This suggests that these NSCLC cells have become dependent on the GSK3 pathway for proliferation during tumourigenesis. Consistent with the role of GSK3 in supporting a tumour phenotype, its inhibition has been shown to promote apoptosis in NSCLC cell lines [43] , [44] . By contrast we found that proliferation of another NSCLC cell line, A549 was insensitive to GSK3 inhibition.…”

Section: Discussionsupporting

confidence: 53%

Glycogen Synthase Kinase 3 Protein Kinase Activity Is Frequently Elevated in Human Non-Small Cell Lung Carcinoma and Supports Tumour Cell Proliferation

Vincent¹,

Elder

O’Flaherty

et al. 2014

PLoS ONE

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BackgroundGlycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC.MethodsThe expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture.ResultsExpression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/β at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes.ConclusionNSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC.

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Section: Discussionsupporting

confidence: 53%

Glycogen Synthase Kinase 3 Protein Kinase Activity Is Frequently Elevated in Human Non-Small Cell Lung Carcinoma and Supports Tumour Cell Proliferation

Vincent¹,

Elder

O’Flaherty

et al. 2014

PLoS ONE

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“…Previous studies showed that xanthatin had an antitumour effect in several tumour cells, including A549 nonsmall cell lung cancer cells, H1299 nonsmall cell lung cancer cells, B16‐F10 murine melanoma cells, human breast cancer MDA‐MB‐231 cells, HL‐60 cells, the human leukemic mast cell line LAD2, and Chinese hamster ovary cells (Li et al, ; Sanchez‐Lamar et al, ; Takeda, Nishimura, et al, ; Takeda, Noguchi, et al, ; Tao et al, ; Tao et al, ; Tao et al, ; Vera et al, ; Yu et al, ; L. Zhang, Ruan, et al, ). Here, we found that xanthatin significantly inhibited tumour growth in both nude mouse xenograft glioma and rat orthotopic implanted glioma in a dose‐dependent manner.…”

Section: Discussionmentioning

confidence: 99%

The antitumour growth and antiangiogenesis effects of xanthatin in murine glioma dynamically evaluated by dynamic contrast‐enhanced magnetic resonance imaging

Wei

et al. 2018

Phytotherapy Research

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To investigate the suppressive effects of xanthatin on glioma growth in a nude mouse xenograft model and rat orthotopic implantation model using magnetic resonance imaging (MRI) to dynamically monitor the antitumour growth and antiangiogenesis effects of xanthatin. The nude mouse xenograft tumour model and rat orthotopic implantation model were established to observe the antitumour effects of xanthatin in vivo. In the rat orthotopic implanted tumour model, MRI scanning was used to dynamically monitor the antitumour growth effect and evaluate the antiangiogenesis effect of xanthatin. We found that xanthatin at a dose of 0.4 mg/10 g dramatically decreased the growth of xenograft tumours in nude mice. The antiangiogenesis effect of xanthatin C6 glioma was evaluated by dynamic contrast-enhanced (DCE) MRI via comparison of the volume transfer constant (K trans ) value, a parameter that reflects vessel permeability. We found that xanthatin at the doses of 8 and 16 mg/kg significantly decreased the K trans value, which suggests that xanthatin has antiangiogenesis effects. These data demonstrate the suppressive effects of xanthatin on C6 glioma occur via antiangiogenesis. Meanwhile, this study also provides evidence for the application of quantitative parameters of DCE-MRI for dynamically evaluating the growth and angiogenesis of intracranial tumours and for experimental and clinical research.

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“…The disordered intracellular JAK2/STAT3 signaling pathway is frequent in many carcinomas and is related to malignant features; therefore, blocking of this pathway can help decrease tumor burden and to improve chemosensitivity. The inhibition of GSK-3β is crucial for xanthation to exert its anticancer properties in NSCLC, and the restraint of inherent activation of STAT3 enhances this function [ 42 ]. C14orf166 has been found to participate in the development of cervical cancer, which is thought to be involved in the abnormal JAK2/STAT3 pathway [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpressed C14orf166 associates with disease progression and poor prognosis in non-small-cell lung cancer

Zhou

Duan

et al. 2018

Bioscience Reports

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Chromosome 14 ORF 166 (C14orf166), a protein involved in the regulation of RNA transcription and translation, has been reported to possess the potency to promote tumorigenesis; however, the role of C14orf166 in non-small-cell lung cancer (NSCLC) remains unknown. The purpose of the present study was to assess C14orf166 expression and its clinical significance in NSCLC. Immunohistochemical staining, quantitative real-time PCR (qRT-PCR), and Western blotting were used to detect the C14orf166 protein and mRNA expression levels in NSCLC tissues compared with adjacent normal tissues, as well as in NSCLC cells lines compared with normal human bronchial epithelial cells (HBE). Then, the correlations between the C14orf166 expression levels and the clinicopathological features of NSCLC were analyzed. Additionally, the Cox proportional hazard model was used to evaluate the prognostic significance of C14orf166. We found that C14orf166 expression increased in carcinoma tissues compared with their adjacent normal tissues at the protein (P<0.001) and mRNA levels (P<0.001). High expression of C14orf166 was significantly associated with the T stage (P=0.006), lymph node metastasis (P=0.001), advanced TNM stage (P<0.001), and chemotherapy (P<0.001). Moreover, according to the survival analysis, patients with overexpressed C14orf166 were inclined to experience a shorter overall survival and disease-free survival time (P<0.001). Multivariate COX analysis implied that C14orf166 was an independent prognostic biomarker. Taken together, our findings indicate that the overexpression of C14orf166 may contribute to the disease progression of NSCLC, represent a novel prognostic predictor and help high-risk patients make better decisions for subsequent therapy.

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Concerted Suppression of STAT3 and GSK3β Is Involved in Growth Inhibition of Non-Small Cell Lung Cancer by Xanthatin

Cited by 22 publications

References 42 publications

Glycogen Synthase Kinase 3 Protein Kinase Activity Is Frequently Elevated in Human Non-Small Cell Lung Carcinoma and Supports Tumour Cell Proliferation

Glycogen Synthase Kinase 3 Protein Kinase Activity Is Frequently Elevated in Human Non-Small Cell Lung Carcinoma and Supports Tumour Cell Proliferation

The antitumour growth and antiangiogenesis effects of xanthatin in murine glioma dynamically evaluated by dynamic contrast‐enhanced magnetic resonance imaging

Overexpressed C14orf166 associates with disease progression and poor prognosis in non-small-cell lung cancer

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