A novel cell-penetrating peptide suppresses breast tumorigenesis by inhibiting β-catenin/LEF-1 signaling.

Tsung-Hua Hsieh,Po-Lin Kuo,Chia-Yi Hsu,Cheng-Yu Long,Tsu-Nai Wang,Shih-Shin Liang,Cheng-Fang Tsai,Eing-Mei Tsai,Chien-Chih Chiu

doi:10.1038/srep19156

Abstract

The inhibition of β-catenin/LEF-1 signaling is an emerging strategy in cancer therapy. However, clinical targeted treatment of the β-catenin/LEF-1 complex remains relatively ineffective. Therefore, development of specific molecular targets is a key approach for identifying new cancer therapeutics. Thus, we attempted to synthesize a peptide (TAT-NLS-BLBD-6) that could interfere with the interaction of β-catenin and LEF-1 at nuclei in human breast cancer cells. TAT-NLS-BLBD-6 directly interacted with β-catenin and inhibited breast cancer cell growth, invasion, migration, and colony formation as well as increased arrest of sub-G1 phase and apoptosis; it also suppressed breast tumor growth in nude mouse and zebrafish xenotransplantation models, showed no signs of toxicity, and did not affect body weight. Furthermore, the human global gene expression profiles and Ingenuity Pathway Analysis software showed that the TAT-NLS-BLBD-6 downstream target genes were associated with the HER-2 and IL-9 signaling pathways. TAT-NLS-BLBD-6 commonly down-regulated 27 candidate genes in MCF-7 and MDA-MB-231 cells, which are concurrent with Wnt downstream target genes in human breast cancer. Our study suggests that TAT-NLS-BLBD-6 is a promising drug candidate for the development of effective therapeutics specific for Wnt/β-catenin signaling inhibition.

Highlights

In the current study, we synthesized a small peptide to block the interaction between β -catenin and LEF-1
Because stabilized β -catenin translocates into the nucleus to affect TCF-4/LEF-1 binding to Wnt target genes[21], we synthesized TAT-NLS fusion peptides derived from LEF-1 to analyze their effects on β -catenin-mediated signaling in the nuclei of breast cancer cells
We chemically synthesized six peptides with a variable region of the β-catenin/LEF-1 binding domain and one mutated version of BLBD-6 to find the capacity of these peptides to suppress cancer cell growth (Fig. 1a)

Summary

Introduction

We synthesized a small peptide to block the interaction between β -catenin and LEF-1. Results TAT-NLS-BLBD-6 inhibits the growth of breast cancer cells. Because stabilized β -catenin translocates into the nucleus to affect TCF-4/LEF-1 binding to Wnt target genes[21], we synthesized TAT-NLS fusion peptides derived from LEF-1 to analyze their effects on β -catenin-mediated signaling in the nuclei of breast cancer cells.

Results

Conclusion