New Therapeutic Approach for Targeting Hippo Signalling Pathway

• Published in: Scientific reports Vol. 9; no. 1; p. 4771
• Main Authors: Dominguez-Berrocal, Leticia, Cirri, Erica, Zhang, Xiguang, Andrini, Laura, Marin, Gustavo H., Lebel-Binay, Sophie, Rebollo, Angelita
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.03.2019; Nature Publishing Group
• Subjects: 13; 13/31; 14; 14/63; 631/67; 64; 64/60; 692/308; 82; 82/1; 96; 96/31; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Amino acids; Animals; Apoptosis; Apoptosis - drug effects; Bacteriology; Breast cancer; Breast Neoplasms - drug therapy; Cell Line, Tumor; Cell Nucleus - metabolism; Deregulation; DNA-Binding Proteins - antagonists & inhibitors; Drug Delivery Systems; Female; Flow cytometry; Fluorescence microscopy; Humanities and Social Sciences; Humans; Life Sciences; Localization; Male; Mice; Mice, Inbred C3H; Microbiology and Parasitology; multidisciplinary; Nuclear Localization Signals - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Nuclear transport; Peptides; Peptides - pharmacology; Protein Transport - drug effects; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Transcription factors; Transcription Factors - antagonists & inhibitors; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts; Yes-associated protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-41404-w

Nuclear localization signals are short amino acid sequences that target proteins for nuclear import. In this manuscript, we have generated a chimeric tri-functional peptide composed of a cell penetrating peptide (CPP), a nuclear localization sequence and an interfering peptide blocking the interaction between TEAD and YAP, two transcription factors involved in the Hippo signalling pathway, whose deregulation is related to several types of cancer. We have validated the cell penetration and nuclear localization by flow cytometry and fluorescence microscopy and shown that the new generated peptide displays an apoptotic effect in tumor cell lines thanks to the specific nuclear delivery of the cargo, which targets a protein/protein interaction in the nucleus. In addition, the peptide has an anti-tumoral effect in vivo in xenograft models of breast cancer. The chimeric peptide designed in the current study shows encouraging prospects for developing nuclear anti- neoplastic drugs.