Aspirin Suppresses the Growth and Metastasis of Osteosarcoma through the NF-κB Pathway

Liao, Dan; Zhong, Li; Duan, Tingmei; Zhang, Ru Hua; Wang, Xin; Wang, Gang; Hu, Kaishun; Lv, Xiaobin; Kang, Tiebang

doi:10.1158/1078-0432.ccr-15-0198

Cited by 104 publications

(96 citation statements)

References 46 publications

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“…NF-κB is constitutively activated in a variety of human malignancies including prostate cancer and it could regulate the expression of many growth genes and the cell biological behavior [15, 28]. Thus, the role of NF-κB was determined in the cell invasion after aspirin treatment.…”

Section: Resultsmentioning

confidence: 99%

“…These processes lead to the liberated NF-κB entering the nucleus and regulation of a variety of downstream target genes [14]. Recently, it has been demonstrated that blockade of the NF-κB activation suppresses the release of many mediators by the cells, eventually modulating the cell survival, invasion, proliferation and death [12, 15]. Therefore, modulation of NF-κB and the related gene expression is though to be important for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

“…The anti-inflammatory activity of aspirin has been proposed through inhibiting cyclooxygenase-2, NF-κB, iNOS and various cytokines [15, 16]. Many studies have focused on aspirin and its ability to inhibit the invasion of a number of cancer cells, including breast, colon, oesophageal and lung cancer cells [17, 18].…”

Section: Introductionmentioning

confidence: 99%

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Aspirin Inhibits IKK-β-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator

Shi

Zhang

Feng

et al. 2017

Cell Physiol Biochem

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Background/Aims: Aspirin has been demonstrated to possess potent chemopreventive and anticancer effects on prostate cancer. However, the more detailed molecular mechanisms of aspirin to suppress prostate cancer cell invasion have not been clearly elucidated. Methods: Transwell assays were performed to evaluate the effects of aspirin on cell invasion. Matrix metalloproteinases (MMPs) and serine proteinases activities in cell media were examined by gelatin zymography and ELISA. In addition, inhibitor of κB (IκB) kinase-β (IKK-β) phosphorylation and IKK-β kinase activity were measured to assess the effects of aspirin on IKK-β activation. Results: We found that aspirin suppressed the invasion and attachment in human prostate cancer cells. Aspirin treatment significantly resulted in reduction of matrix metalloproteinase-9 (MMP-9) and upregulation of tissue inhibitors of metalloproteinase-1 (TIMP-1) activity, which are the proteolytic enzymes contributing to the degradation of extracellular matrix and basement membrane in cell invasion and metastasis. Our data further showed that aspirin was able to inhibit both urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) expression in the cells. In addition, aspirin treatment caused a strong decrease in nuclear factor-kappa B (NF-κB) activation, inhibitor of κB (IκB)-α phosphorylation together with translocation of NF-κB p65 to nucleus and IκB kinase (IKK)- β activation. Moreover, the inhibitory effects of aspirin on cell invasion were reversed by IKK-β overexpression, while the IKK inhibitor sensitizes the anti-invasive effect of aspirin in prostate cancer cells. Conclusion: The present research concluded that aspirin suppressed prostate cancer cell invasion by reducing MMP-9 activity and uPA expression through decreasing of IKK-β-mediated NF-κB activation, indicating that the ability of aspirin to inhibit cell invasion might be useful in the chemoprevention of metastatic prostate cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aspirin Inhibits IKK-β-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator

Shi

Zhang

Feng

et al. 2017

Cell Physiol Biochem

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“…An apparent discrepancy is that the concentrations required to exert these effects in cancer cells were significantly higher than that required to inhibit the activity of COX-1 or COX-2, suggesting the implications of other potential targets (12,13). Indeed, cell-based studies have demonstrated that aspirin inhibits cell proliferation, induces cell-cycle arrest and apoptosis in multiple cancer cell lines irrespective of COX-2 expression level (14)(15)(16)(17)(18). Aspirin can also sensitize cancer cell to TRAIL-induced apoptosis through a COX-2-independent mechanism (19).…”

Section: Introductionmentioning

confidence: 99%

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Dai

Yan

et al. 2017

Clinical Cancer Research

104

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Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of smallmolecule inhibitors of heparanase.

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“…Aspirin has been shown to be a potential agent for cancer chemoprevention, especially in colorectal cancer [14, 15], by inducing cancer cell apoptosis and inhibiting cell proliferation [16, 17]. Recently, aspirin has attracted strong attention for its effect on metastasis inhibition [18-21] and chemotherapy sensitivity improvement [22, 23]. Moreover, aspirin inhibits cancer cells proliferation and induces cancer cell apoptosis by preventing NF-κB activation [24, 25], interfering with ERK pathway [26] and inhibiting Wnt/β-catenin pathway [27].…”

Section: Introductionmentioning

confidence: 99%

Reduction of NANOG Mediates the Inhibitory Effect of Aspirin on Tumor Growth and Stemness in Colorectal Cancer

Wang¹,

Liu²,

Wang³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Cancer stem cells (CSCs) are considered to be responsible for tumor relapse and metastasis, which serve as a potential therapeutic target for cancer. Aspirin has been shown to reduce cancer risk and mortality, particularly in colorectal cancer. However, the CSCs-suppressing effect of aspirin and its relevant mechanisms in colorectal cancer remain unclear. Methods: CCK8 assay was employed to detect the cell viability. Sphere formation assay, colony formation assay, and ALDH1 assay were performed to identify the effects of aspirin on CSC properties. Western blotting was performed to detect the expression of the stemness factors. Xenograft model was employed to identify the anti-cancer effects of aspirin in vivo. Unpaired Student t test, ANOVA test and Kruskal-Wallis test were used for the statistical comparisons. Results: Aspirin attenuated colonosphere formation and decreased the ALDH1 positive cell population of colorectal cancer cells. Aspirin inhibited xenograft tumor growth and reduced tumor cells stemness in nude mice. Consistently, aspirin decreased the protein expression of stemness-related transcription factors, including c-Myc, OCT4 and NANOG. Suppression of NANOG blocked the effect of aspirin on sphere formation. Conversely, ectopic expression of NANOG rescued the aspirin-repressed sphere formation, suggesting that NANOG is a key downstream target. Moreover, we found that aspirin repressed NANOG expression in protein level by decreasing its stability. Conclusion: We have provided new evidence that aspirin attenuates CSC properties through down-regulation of NANOG, suggesting aspirin as a promising therapeutic agent for colorectal cancer treatment.

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Aspirin Suppresses the Growth and Metastasis of Osteosarcoma through the NF-κB Pathway

Cited by 104 publications

References 46 publications

Aspirin Inhibits IKK-β-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator

Aspirin Inhibits IKK-β-mediated Prostate Cancer Cell Invasion by Targeting Matrix Metalloproteinase-9 and Urokinase-Type Plasminogen Activator

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Reduction of NANOG Mediates the Inhibitory Effect of Aspirin on Tumor Growth and Stemness in Colorectal Cancer

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