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Abstract
Introduction/Background The clinical application of Melittin is limited by its non-specific cytotoxicity and hemolytic activity. Here, we synthesized a novel antineoplastic peptide UM-6 based on melittin and explored the mechanism related to its anti-proliferation and metastasis on cervical cancer.
Methodology The function of UM-6 on proliferation, invasion, and migration was assessed by MTT assay, colony formation assay, transwell assay, and 3D invasion assay. To identify the anti-tumor molecular mechanism of UM-6,we used flow cytometry, immunoprecipitation, real-time quantitative PCR, dual-luciferase reporter assay, Western Blot, immunofluorescence, and immunohistochemistry. Finally, mouse xenograft models were constructed to further investigate the role of UM-6 in inhibiting cervical cancer proliferation and metastasis in vivo.
Results Firstly, UM-6 inhibits the proliferation of cervical cancer cells and less cytotoxic to normal epithelial cells in vitro; Secondly, UM-6 inhibits the invasion and migration of cervical cancer cells in vitro; Thirdly, UM-6 induces apoptosis and autophagosome accumulation in cervical cancer cells; Concretely, UM-6 promotes autophagic flux by promoting autophagosome degradation, and blocking autophagy reverses UM-6-induced cell death. Thus, we discovered that UM-6 inhibited cervical cancer cell viability while also inducing apoptosis (type I cell death) and autophagy-dependent cell death (type II cell death). UM-6 triggers the Hippo signaling pathway and promotes cytoplasmic retention and phosphorylation-dependent degradation of YAP; inhibits YAP-TEAD binding and reduces transcriptional activity, thereby suppressing the expression of downstream target genes. Injection of UM-6 in mice can significantly inhibit the growth of xenograft tumors without significant toxicity, and greatly reduce the number, volume, and burden of abdominal tumors in the metastasis model driven by cervical cancer cell lines.
Conclusion UM-6 has the potential to serve as a new anticancer drug candidate. As a regulator of apoptosis and autophagy, UM-6 also regulates the Hippo/YAP pathway, providing a new avenue for efficient anti-cervical cancer therapy.