Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model
| Autor: | Madhulika Dixit, Jaganathan Kowshik, Kumaraswamy Anbarasu, Siddavaram Nagini, Sundarasamy Mahalingam, Satabdi Rautray, G. Deepak Reddy, Rajakishore Mishra, Josephraj Sophia |
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| Rok vydání: | 2017 |
| Předmět: |
Limonins
Male 0301 basic medicine Angiogenesis Science Notch signaling pathway Hamster Biology Matrix metalloproteinase GPI-Linked Proteins medicine.disease_cause Article 03 medical and health sciences Downregulation and upregulation Cell Line Tumor Cricetinae medicine Animals Gene knockdown Multidisciplinary Neovascularization Pathologic Hypoxia-Inducible Factor 1 alpha Subunit Immunohistochemistry Gene Expression Regulation Neoplastic MicroRNAs Cell Transformation Neoplastic 030104 developmental biology Cell culture Immunology Cancer research Medicine RNA Interference Carcinogenesis Signal Transduction |
| Zdroj: | Scientific Reports Scientific Reports, Vol 7, Iss 1, Pp 1-12 (2017) |
| ISSN: | 2045-2322 |
| Popis: | Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a potent inhibitor of matrix metalloproteinases (MMPs) is a common negative target of oncogenic signals and a potential therapeutic target for novel drug development. Here, we show that sequential RECKlessness stimulates angiogenesis and Notch signalling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model, a paradigm for oral oncogenesis and chemointervention. We also report the chemotherapeutic effect of nimbolide, a limonoid from the neem tree (Azadirachta indica) based on the upregulation of RECK as well as modulation of the expression of key molecules involved in invasion and angiogenesis. We demonstrate that nimbolide upregulates RECK by targeting miR-21, and HIF-1α resulting in reduced MMP activity and blockade of VEGF and Notch signalling. Nimbolide reduced microvascular density, confirming its anti-angiogenic potential. Molecular docking analysis revealed interaction of nimbolide with HIF-1α. Additionally, we demonstrate that nimbolide upregulates RECK expression via downregulation of HIF-1α and miR-21 by overexpression and knockdown experiments in SCC4 and EAhy926 cell lines. Taken together, these findings provide compelling evidence that targeting RECK, a keystone protein that regulates mediators of invasion and angiogenesis with phytochemicals such as nimbolide may be a robust therapeutic approach to prevent oral cancer progression. |
| Databáze: | OpenAIRE |
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