Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP‐2/9 expression via inhibiting ERK1/2 and reducing DNA‐binding activity of NF‐κB in colon cancer cells

Babykutty, Suboj; Priya, Patel; Nandini, Ravikumar Jayakumari; Kumar, Mukesh; Nair, Mangalam S.; Srinivas, Priya; Gopala, Srinivas

doi:10.1002/mc.20812

Cited by 105 publications

(100 citation statements)

References 46 publications

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“…5C) [15]. Many studies had indicated that ERK1/2 and AKT were involved in activities of MMP2 and MMP9 [16,17,18]. To assess whether the suppressed expression of MMP2 and MMP9 was mediated by the inhibition of AKT and ERK1/2 pathways, we investigated the effect of AXIIR siRNA on phosphorylation of AKT and ERK1/2.…”

Section: Resultsmentioning

confidence: 99%

SiRNA Directed Against Annexin II Receptor Inhibits Angiogenesis via Suppressing MMP2 and MMP9 Expression

Song

Pan

Sun

et al. 2015

Cell Physiol Biochem

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Background/Aims: Annexin II receptor (AXIIR) is able to mediate Annexin II signal and induce apoptosis, but its role in angiogenesis remains unclear. This study tries to investigate the role of AXIIR in angiogenesis and the plausible molecular mechanism. Methods/Results: RNA interference technology was used to silence AXIIR, and the subsequent effects in vitro and in vivo were evaluated thereafter. Our data indicated that human umbilical vein endothelial cells (HUVECs) expressed AXIIR and knockdown of AXIIR significantly inhibited HUVECs proliferation, adhesion, migration, and tube formation in vitro and suppressed angiogenesis in vivo. Furthermore, AXIIR siRNA induced cell arrest in the S/G2 phase while had no effect on cell apoptosis. We found that these subsequent effects might be via suppressing the expression of matrix metalloproteinase 2and matrix metalloproteinase 9. Conclusion: AXIIR participates in angiogenesis, and may be a potential therapeutic target for angiogenesis related diseases.

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Section: Resultsmentioning

confidence: 99%

SiRNA Directed Against Annexin II Receptor Inhibits Angiogenesis via Suppressing MMP2 and MMP9 Expression

Song

Pan

Sun

et al. 2015

Cell Physiol Biochem

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“…In our studies, we find that aspirin-mediated cell invasion inhibition is reversed by IKK-β overexpression, while the IKK inhibitor sensitizes the anti-invasive effect of aspirin in prostate cancer cells. In addition to NF-κB, there is abundant evidence that the invasive capacity of cancer cells is related to the activation of mitogen-activated protein kinases such as ERK1/2 [43]. Recent studies have demonstrated that the phosphorylation of ERK1/2 promotes MMP secretion and increases prostate cancer cell metastasis [44].…”

Section: Discussionmentioning

confidence: 99%

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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“…Nimbolide, a tetranortriterpenoid limonoid, is one of the important contributors to the cytotoxicity of neem extracts (20). This limonoid has been shown to possess numerous biological activities such as antifeedant (21), antimalarial (22), antimicrobial (23), and anticancer (19, 20, 24–30) activities. The limonoid exhibits antiproliferative activity in a wide variety of tumor cells, including neuroblastoma, osteosarcoma, choriocarcinoma (31), cervical cancer (32), leukemia, and melanoma (29) cells.…”

Section: Introductionmentioning

confidence: 99%

Nimbolide, a Limonoid Triterpene, Inhibits Growth of Human Colorectal Cancer Xenografts by Suppressing the Proinflammatory Microenvironment

Gupta

Prasad

Sethumadhavan

et al. 2013

Clinical Cancer Research

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Purpose Extensive research over the past decade has revealed that the proinflammatory microenvironment plays a critical role in the development of colorectal cancer (CRC). Whether nimbolide, a limonoid triterpene, can inhibit the growth of CRC was investigated in the present study. Experimental Design The effect of nimbolide on proliferation of CRC cell lines was examined by MTT assay, apoptosis by caspase activation and poly-ADP ribose polymerase cleavage, nuclear factor-kappa B (NF-kB) activation by DNA-binding assay, and protein expression by Western blotting. The effect of nimbolide on the tumor growth in vivo was examined in CRC xenografts in a nude mouse model. Results Nimbolide inhibited proliferation, induced apoptosis, and suppressed NF-κB activation and NF-κB–regulated tumorigenic proteins in CRC cells. The suppression of NF-κB activation by nimbolide was caused by sequential inhibition of IκB kinase (IKK) activation, IκBα phosphorylation, and p65 nuclear translocation. Furthermore, the effect of nimbolide on IKK activity was found to be direct. In vivo, nimbolide (at 5 and 20 mg/kg body weight), injected intraperitoneally after tumor inoculation, significantly decreased the volume of CRC xenografts. The limonoid-treated xenografts exhibited significant down-regulation in the expression of proteins involved in tumor cell survival (Bcl-2, Bcl-xL, c-IAP-1, survivin, Mcl-1), proliferation (c-Myc, cyclin D1), invasion (MMP-9, ICAM-1), metastasis (CXCR4), and angiogenesis (VEGF). The limonoid was found to be bioavailable in the blood plasma and tumor tissues of treated mice. Conclusions Our studies provide evidence that nimbolide can suppress the growth of human CRC through modulation of the proinflammatory microenvironment.

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Nimbolide retards tumor cell migration, invasion, and angiogenesis by downregulating MMP‐2/9 expression via inhibiting ERK1/2 and reducing DNA‐binding activity of NF‐κB in colon cancer cells

Cited by 105 publications

References 46 publications

SiRNA Directed Against Annexin II Receptor Inhibits Angiogenesis via Suppressing MMP2 and MMP9 Expression

SiRNA Directed Against Annexin II Receptor Inhibits Angiogenesis via Suppressing MMP2 and MMP9 Expression

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

Nimbolide, a Limonoid Triterpene, Inhibits Growth of Human Colorectal Cancer Xenografts by Suppressing the Proinflammatory Microenvironment

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