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Published on: August 25, 2021
Repurposing mebendazole to reprogram oncogenic and tumor-suppressor networks: Multi-cancer insights from ENOX2, MMP2,
Rasha Shaker Aqel1, Areej Sami Ismail1, Mohamed El-Tanani2
1Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan.
Background:
Cancer progression involves coordinated regulation of oncogenes and tumor suppressors. This study explores the interplay of ENOX2 (ecto-NADH oxidase disulfide-thiol exchanger 2), MMP2 (matrix metalloproteinase-2), and regulatory genes Ras Association Domain Family Member 1, Isoform A (RASSF1A), WAP Four-Disulfide Core Domain Protein 10A (WFDC10A), and Methyltransferase-Like Protein 7A (METTL7A) across multiple cancer cell lines, and evaluates the anticancer potential of repurposed mebendazole.
Methods:
Eight human cell lines, including breast (MCF7 and MDAMB231), colorectal, pancreatic, lung, hepatocellular, leukemia, and endothelial models, were profiled by qRT-PCR and Western blotting. Expression was assessed under basal conditions and following mebendazole exposure (0.7 µM).
Results:
Basal expression revealed elevated ENOX2 and MMP2 in aggressive cancers (MDA-MB-231, PANC1). Mebendazole significantly downregulated ENOX2 in HEPG2 (p < 0.01) and K562 (p < 0.05), and suppressed MMP2 in MDA-MB-231 (p < 0.05) and MCF7 (p < 0.01), indicating anti-invasive effects. Tumor suppressors were selectively induced: RASSF1A increased >200-fold in endothelial cells (p < 0.01) and was upregulated in HEPG2 and HT29 (p < 0.05), while WFDC10A was strongly elevated in MDA-MB-231 (>40-fold, p < 0.001). METTL7A displayed endothelial enrichment with heterogeneous tumor-specific regulation. Collectively, these findings reveal cell-type-specific modulation of oncogenic and suppressor pathways.
Conclusion:
This multi-cancer investigation identifies ENOX2-MMP2 signaling as a functional driver of invasion and metastasis and demonstrates that mebendazole reprograms oncogenic-tumor suppressor networks. By integrating biomarker profiling with drug repurposing, our study highlights the translational potential of mebendazole as a cost-effective anticancer agent and supports the development of multi-gene biomarkers for diagnosis and therapy in aggressive malignancies.
Insights
Mebendazole reprograms cancer cell networks by downregulating oncogenes ENOX2 and MMP2, and upregulating tumor suppressors RASSF1A and WFDC10A, showing potential as an anticancer agent.
Area of Science:
- Oncology
- Molecular Biology
- Drug Repurposing
Background:
- Cancer progression involves complex regulation of oncogenes and tumor suppressors.
- This study investigates the interplay of ENOX2, MMP2, RASSF1A, WFDC10A, and METTL7A in various cancer cell lines.
- The anticancer potential of repurposed mebendazole is evaluated.
Purpose of the Study:
- To explore the regulatory network of specific oncogenes and tumor suppressors in cancer.
- To assess the impact of mebendazole on these regulatory genes.
- To identify potential biomarkers for cancer diagnosis and therapy.
Main Methods:
- Utilized qRT-PCR and Western blotting to profile eight human cancer cell lines.
- Assessed gene expression under basal conditions and after mebendazole treatment (0.7 µM).
Main Results:
- Elevated ENOX2 and MMP2 were observed in aggressive cancer cell lines.
- Mebendazole significantly downregulated ENOX2 and MMP2, indicating anti-invasive effects.
- Tumor suppressors RASSF1A and WFDC10A were selectively induced by mebendazole, with cell-type-specific modulation observed for METTL7A.
Conclusions:
- ENOX2-MMP2 signaling drives invasion and metastasis in cancer.
- Mebendazole effectively reprograms oncogenic-tumor suppressor networks.
- Mebendazole shows translational potential as a cost-effective anticancer agent, supporting multi-gene biomarker development for aggressive malignancies.
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