Short Peptides based on the conserved regions of MIEN1 protein exhibit anti-cancer activity by targeting the MIEN1 Signaling Pathway

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dc.creatorTripathi, Amit K.
dc.creatorDesai, Priyanka P.
dc.creatorTyagi, Antariksh
dc.creatorLampe, Jana B.
dc.creatorSrivastava, Yogesh
dc.creatorDonkor, Michael
dc.creatorJones, Harlan P.
dc.creatorDzyuba, Sergei V.
dc.creatorCrossley, Eric
dc.creatorWilliams, Noelle S.
dc.creatorVishwanatha, Jamboor K.
dc.creator.orcid0000-0002-0266-6020 (Vishwanatha, Jamboor K.)
dc.creator.orcid0000-0003-3248-0355 (Jones, Harlan P.)
dc.date.accessioned2024-03-21T14:26:55Z
dc.date.available2024-03-21T14:26:55Z
dc.date.issued2024-01-26
dc.description.abstractMigration and invasion enhancer 1 (MIEN1) overexpression characterizes several cancers and facilitates cancer cell migration and invasion. Leveraging conserved ITAM and prenylation motifs within MIEN1, we identified potent anti-cancer peptides. Among them, bioactive peptides LA3IK and RP-7 induced pronounced transcriptomic and protein expression changes at sub-IC50 concentrations. The peptides effectively inhibited genes and proteins driving cancer cell migration, invasion, and EMT pathways, concurrently suppressing EGF-induced NF-kappaB nuclear translocation in metastatic breast cancer cells. Specifically, peptides targeted the same signal transduction pathway initiated by MIEN1. Molecular docking and circular dichroism spectroscopy indicated the formation of MIEN1-peptide complexes. The third-positioned isoleucine in LA3IK and CVIL motif in RP-7 were crucial for inhibiting breast cancer cell migration. This is evident from the limited migration inhibition observed when MDA-MB-231 cells were treated with scrambled peptides LA3IK SCR and RP-7 SCR. Additionally, LA3IK and RP-7 effectively suppressed tumor growth in an orthotopic breast cancer model. Notably, mice tolerated high peptide doses of up to 90 mg/Kg well, surpassing significantly lower doses of 5 mg/Kg intravenously (iv) and 30 mg/Kg intraperitoneally (ip) used in both in vivo pharmacokinetic studies and orthotopic mouse model assays. D-isomers of LA3IK and RP-7 showed enhanced anti-cancer activity compared to their L-isomers. D-LA3IK remained stable in mouse plasma for 24 h with 75% remaining, exhibiting superior pharmacokinetic properties over D/L-RP-7. In summary, our findings mark the first report of short peptides based on MIEN1 protein sequence capable of inhibiting cancer signaling pathways, effectively impeding cancer progression both in vitro and in vivo.
dc.identifier.citationTripathi, A. K., Desai, P. P., Tyagi, A., Lampe, J. B., Srivastava, Y., Donkor, M., Jones, H. P., Dzyuba, S. V., Crossley, E., Williams, N. S., & Vishwanatha, J. K. (2024). Short peptides based on the conserved regions of MIEN1 protein exhibit anticancer activity by targeting the MIEN1 signaling pathway. The Journal of biological chemistry, 300(3), 105680. Advance online publication. https://doi.org/10.1016/j.jbc.2024.105680
dc.identifier.issn1083-351X
dc.identifier.urihttps://hdl.handle.net/20.500.12503/32509
dc.publisherElsevier B.V.
dc.relation.urihttps://doi.org/10.1016/j.jbc.2024.105680
dc.rights.holder© 2024 THE AUTHORS.
dc.rights.licenseAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceJournal of Biological Chemistry
dc.subjectanti-cancer peptides
dc.subjectbreast cancer
dc.subjectpeptide design
dc.subjectcancer biology
dc.subjectepidermal growth factor (EGF)
dc.subjectepithelial-mesenchymal transition (EMT)
dc.subjectpharmacokinetics
dc.subjectprotein motif
dc.titleShort Peptides based on the conserved regions of MIEN1 protein exhibit anti-cancer activity by targeting the MIEN1 Signaling Pathway
dc.typeArticle
dc.type.materialtext

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