First-in-class Peptide Molecules Targeting the MIEN1 Cancer signaling Pathway for which no inhibitors are currently identified

dc.creatorTripathi, Amiten_US
dc.creatorRanade, Payalen_US
dc.creatorTrivedi, Ruchaen_US
dc.creatorVishwanatha, Jamboor K.en_US
dc.creator.orcid0000-0002-3784-8799 (Tripathi, Amit)
dc.descriptionResearch Appreciation Day Award Winner - School of Biomedical Sciences, 2024 Postdoctoral Oral Presentation Awarden_US
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-kB 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.en_US
dc.description.sponsorshipThis work was supported by awards from the National Institute of Health under awards R01CA220273, U54MD006882 ,S21MD012472 and Summerfield G. Roberts foundation grant to Dr. Jamboor K. Vishwanatha.en_US
dc.titleFirst-in-class Peptide Molecules Targeting the MIEN1 Cancer signaling Pathway for which no inhibitors are currently identifieden_US