Nimbolide upregulates RECK by targeting miR-21 and HIF-1α in cell lines and in a hamster oral carcinogenesis model View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-05-17

AUTHORS

Jaganathan Kowshik, Rajakishore Mishra, Josephraj Sophia, Satabdi Rautray, Kumaraswamy Anbarasu, G. Deepak Reddy, Madhulika Dixit, Sundarasamy Mahalingam, Siddavaram Nagini

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. More... »

PAGES

2045

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-01960-5

DOI

http://dx.doi.org/10.1038/s41598-017-01960-5

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1085379715

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28515436


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92 motif
93 neem tree
94 negative targets
95 nimbolide
96 novel drug development
97 oncogenesis
98 oncogenic signals
99 oral cancer progression
100 oral carcinogenesis model
101 oral oncogenesis
102 overexpression
103 paradigm
104 phytochemicals
105 potent inhibitor
106 potential
107 potential therapeutic target
108 pouch (HBP) carcinogenesis model
109 progression
110 protein
111 recklessness
112 reduced MMP activity
113 reversion-inducing cysteine-rich protein
114 robust therapeutic approach
115 sequential RECKlessness
116 signals
117 target
118 therapeutic approaches
119 therapeutic target
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