Short peptides based on the conserved regions of MIEN1 protein exhibit anticancer activity by targeting the MIEN1 signaling pathway

Sep 21, 2026

Uploaded by Patrick

Migration and invasion enhancer 1 (MIEN1) overexpression characterizes multiple cancers and promotes malignant cell migration, invasion, and epithelial–mesenchymal transition. Conserved immunoreceptor tyrosine-based activation motif and prenylation motifs within MIEN1 were used to identify potent anticancer peptides. LA3IK and RP-7 drove pronounced transcriptomic and protein changes at sub-IC50 levels, suppressing MIEN1-pathway targets of migration and invasion and inhibiting NF-κB nuclear translocation. Docking and CD spectra supported MIEN1–peptide complex formation, crucial residues were defined, and peptide effects were validated in vitro and in an orthotopic breast cancer model with favorable tolerability in mice.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

Background and rationale

MIEN1 structure and functional motifs

Results

Peptide design

RESEARCH ARTICLE Short peptides based on the conserved regions of MIEN1 protein exhibit anticancer activity by targeting the MIEN1 signaling pathway Received for publication, September 23, 2023, and in revised form, January 6, 2024 Published, Papers in Press, January 23, 2024, [https://doi.org/10.1016/j.jbc.2024.105680](https://doi.org/10.1016/j.jbc.2024.105680) Amit K. Tripathi 1, *, Priyanka P. Desai 1, Antariksh Tyagi2, Jana B. Lampe 1, Yogesh Srivastava3, Michael Donkor 1, Harlan P. Jones 1, Sergei V. Dzyuba4, Eric Crossley5, Noelle S. Williams5, and Jamboor K. Vishwanatha 1, * From the 1Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, Texas, USA; 2 Yale Center for Genome Analysis (YCGA), Yale School of Medicine, New Haven, Connecticut, USA; 3Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 4Department of Chemistry and Biochemistry, Texas Christian University, Fort Worth, Texas, USA; 5Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA Reviewed by members of the JBC Editorial Board. Edited by Enrique De La Cruz Migration and invasion enhancer 1 (MIEN1) overexpression characterizes several cancers and facilitates cancer cell migration and invasion. Leveraging conserved immunoreceptor tyrosine-based activation motif and prenylation motifs within MIEN1, we identiﬁed potent anticancer 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 epithelialmesenchymal transition pathways, concurrently suppressing epidermal growth factor-induced nuclear factor kappa B nuclear translocation in metastatic breast cancer cells. Specifically, peptides targeted the same signal transduction pathway initiated by MIEN1. Molecular docking and CD spectra indicated the formation of MIEN1-peptide complexes. The thirdpositioned 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 intraperitoneal (ip) peptide doses of 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 anticancer 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. * For correspondence: Amit K. Tripathi, [amitkumar.tripathi@unthsc.edu](amitkumar.tripathi@unthsc.edu); Jamboor K. Vishwanatha, [Jamboor.Vishwanatha@unthsc.edu](Jamboor.Vishwanatha@unthsc.edu). Discovering novel strategies for cancer treatment is a pressing priority within the realm of cancer therapeutics. While chemotherapy remains the prevailing approach, its efﬁcacy is often hampered by its indiscriminate toxicity toward normal cells and the necessity for high drug dosages. This frequently leads to the emergence of chemoresistance, a major factor in treatment failures of both breast and prostate cancer cells (1, 2). Moreover, the highly heterogeneous nature of triple-negative breast cancer (TNBC) and the absence of three key receptors present a signiﬁcant hindrance to successful treatment (3). Anticancer peptides (ACPs) have been shown to s

FAQs

How were the anticancer peptides designed from MIEN1?

The peptides were derived from conserved immunoreceptor tyrosine-based activation motif and prenylation motifs within MIEN1, using MIEN1’s canonical ITAM sequence information.

What molecular pathway effects did LA3IK and RP-7 show?

LA3IK and RP-7 suppressed genes and proteins driving migration, invasion, and epithelial–mesenchymal transition, and they inhibited EGF-induced NF-κB nuclear translocation in metastatic breast cancer cells.

What evidence supports peptide binding to MIEN1?

Molecular docking and CD spectra indicated formation of MIEN1–peptide complexes, and specific residues were identified as crucial for inhibiting migration.

Sep 21, 2026

Uploaded by Patrick