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RECK and TIMP-2 mediate inhibition of MMP-2 and MMP-9 by Annona muricata
G Drishya1, Jyotsna Nambiar, Sanu K Shaji
1Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri, Clappana P.O, Kollam 690 525, India.
Abstract:
Up-regulation of MMP-2 and MMP-9 plays a significant role in promoting cancer progression by degrading the components of the extracellular matrix, thereby enhancing the migration of tumor cells. Although the antiproliferative and apoptotic effect of Annona muricata is well established, its effect on MMP-2 and MMP-9, a major target in several types of cancers, has not been studied. Powdered samples of various parts of A. muricata like fruit, stem, seed, and twig extracted using aqueous methanol showed significant dose-dependent inhibition of MMP-2 and MMP-9 in a highly metastatic fibrosarcoma cell line, HT1080. Additionally, these extracts also up-regulated the expression of several endogenous inhibitors of MMP-2 and MMP-9 like REversion-inducing Cysteine-rich protein with Kazal motifs (RECK) and Tissue Inhibitor of Metalloproteinase- 2 (TIMP-2). Furthermore, primary cells developed from tumor tissues obtained from patients not exposed to chemotherapy, also exhibited similar results. Remarkably, the inhibition of MMP-2 and MMP-9 observed was tumor specific, with the A. muricata fruit extract showing only 2% inhibition in cells obtained from normal tissues, when compared to 60% inhibition observed in cells obtained from tumor samples. The present study elucidates a novel mechanism by which A. muricata extracts selectively exhibit their anti-cancer activity in tumor cells by down-regulating MMP-2 and MMP-9 that are important biomarkers in cancer.
Insights
Annona muricata extracts inhibit MMP-2 and MMP-9, crucial for cancer spread. This study reveals a novel, tumor-specific mechanism where these extracts down-regulate these matrix metalloproteinases, offering a new avenue for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) are key drivers of cancer progression, facilitating tumor cell migration by degrading extracellular matrix.
- While Annona muricata exhibits known antiproliferative and apoptotic effects, its impact on MMP-2 and MMP-9, significant cancer targets, remains uninvestigated.
Purpose of the Study:
- To investigate the effect of Annona muricata extracts on MMP-2 and MMP-9 activity and expression in cancer cells.
- To explore the potential of Annona muricata as a therapeutic agent by elucidating its mechanism of action against cancer progression.
Main Methods:
- Various parts of Annona muricata were extracted using aqueous methanol.
- The inhibitory effects of these extracts on MMP-2 and MMP-9 were assessed in a highly metastatic fibrosarcoma cell line (HT1080) and primary tumor cells.
- The expression of endogenous MMP inhibitors, RECK and TIMP-2, was analyzed.
Main Results:
- Annona muricata extracts demonstrated significant, dose-dependent inhibition of MMP-2 and MMP-9 in HT1080 cells.
- Extracts also upregulated the expression of MMP inhibitors RECK and TIMP-2.
- The inhibitory effect was tumor-specific, with minimal impact on normal cells (2% inhibition by fruit extract vs. 60% in tumor cells).
Conclusions:
- Annona muricata extracts possess a novel anti-cancer mechanism involving the selective down-regulation of MMP-2 and MMP-9 in tumor cells.
- These findings highlight the therapeutic potential of Annona muricata in targeting cancer progression by modulating key matrix metalloproteinases.
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