Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model
Abstract 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 ang...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2017-05-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-01960-5 |
| _version_ | 1818840963117744128 |
|---|---|
| author | Jaganathan Kowshik Rajakishore Mishra Josephraj Sophia Satabdi Rautray Kumaraswamy Anbarasu G. Deepak Reddy Madhulika Dixit Sundarasamy Mahalingam Siddavaram Nagini |
| author_facet | Jaganathan Kowshik Rajakishore Mishra Josephraj Sophia Satabdi Rautray Kumaraswamy Anbarasu G. Deepak Reddy Madhulika Dixit Sundarasamy Mahalingam Siddavaram Nagini |
| author_sort | Jaganathan Kowshik |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-19T04:18:32Z |
| format | Article |
| id | doaj.art-2e5292f5a45a4f54a69126fff9216ca9 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T04:18:32Z |
| publishDate | 2017-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-2e5292f5a45a4f54a69126fff9216ca92022-12-21T20:36:14ZengNature PortfolioScientific Reports2045-23222017-05-017111210.1038/s41598-017-01960-5Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis modelJaganathan Kowshik0Rajakishore Mishra1Josephraj Sophia2Satabdi Rautray3Kumaraswamy Anbarasu4G. Deepak Reddy5Madhulika Dixit6Sundarasamy Mahalingam7Siddavaram Nagini8Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai UniversityCentre for Life Sciences, School of Natural Sciences, Central University of Jharkhand, Ratu-Lohardaga Road, BrambeDepartment of Biochemistry and Biotechnology, Faculty of Science, Annamalai UniversityDepartment of Biochemistry and Biotechnology, Faculty of Science, Annamalai UniversityDepartment of Biotechnology, Indian Institute of Technology MadrasMedicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and ResearchDepartment of Biotechnology, Indian Institute of Technology MadrasDepartment of Biotechnology, Indian Institute of Technology MadrasDepartment of Biochemistry and Biotechnology, Faculty of Science, Annamalai UniversityAbstract 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.https://doi.org/10.1038/s41598-017-01960-5 |
| spellingShingle | Jaganathan Kowshik Rajakishore Mishra Josephraj Sophia Satabdi Rautray Kumaraswamy Anbarasu G. Deepak Reddy Madhulika Dixit Sundarasamy Mahalingam Siddavaram Nagini Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model Scientific Reports |
| title | Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model |
| title_full | Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model |
| title_fullStr | Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model |
| title_full_unstemmed | Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model |
| title_short | Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model |
| title_sort | nimbolide upregulates reck by targeting mir 21 and hif 1α in cell lines and in a hamster oral carcinogenesis model |
| url | https://doi.org/10.1038/s41598-017-01960-5 |
| work_keys_str_mv | AT jaganathankowshik nimbolideupregulatesreckbytargetingmir21andhif1aincelllinesandinahamsteroralcarcinogenesismodel AT rajakishoremishra nimbolideupregulatesreckbytargetingmir21andhif1aincelllinesandinahamsteroralcarcinogenesismodel AT josephrajsophia nimbolideupregulatesreckbytargetingmir21andhif1aincelllinesandinahamsteroralcarcinogenesismodel AT satabdirautray nimbolideupregulatesreckbytargetingmir21andhif1aincelllinesandinahamsteroralcarcinogenesismodel AT kumaraswamyanbarasu nimbolideupregulatesreckbytargetingmir21andhif1aincelllinesandinahamsteroralcarcinogenesismodel AT gdeepakreddy nimbolideupregulatesreckbytargetingmir21andhif1aincelllinesandinahamsteroralcarcinogenesismodel AT madhulikadixit nimbolideupregulatesreckbytargetingmir21andhif1aincelllinesandinahamsteroralcarcinogenesismodel AT sundarasamymahalingam nimbolideupregulatesreckbytargetingmir21andhif1aincelllinesandinahamsteroralcarcinogenesismodel AT siddavaramnagini nimbolideupregulatesreckbytargetingmir21andhif1aincelllinesandinahamsteroralcarcinogenesismodel |