Small peptide inhibitor from the sequence of RUNX3 disrupts PAK1–RUNX3 interaction and abrogates its phosphorylation-dependent oncogenic function

P21 Activated Kinase 1 (PAK1) is an oncogenic serine/threonine kinase known to play a significant role in the regulation of cytoskeleton and cell morphology. Runt-related transcription factor 3 (RUNX3) was initially known for its tumor suppressor function, but recent studies have reported the oncoge...

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Bibliographic Details
Published in:	Oncogene Vol. 40; no. 34; pp. 5327 - 5341
Main Authors:	Kanumuri, Rahul, Chelluboyina, Aruna Kumar, Biswal, Jayashree, Vignesh, Ravichandran, Pandian, Jaishree, Venu, Akkanapally, Vaishnavi, B., Leena, DJ, Jeyaraman, Jeyakanthan, Ganesan, Kumaresan, Aradhyam, Gopala Krishna, Venkatraman, Ganesh, Rayala, Suresh K.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 26-08-2021 Nature Publishing Group
Subjects:	14/63 45/29 631/337/458 631/80/83 82/83 96/95 Amino acid sequence Animals Apoptosis Cancer Cell Biology Cell culture Cell Line, Tumor Cell Proliferation - drug effects Core Binding Factor Alpha 3 Subunit - genetics Core Binding Factor Alpha 3 Subunit - metabolism Cytology Cytoskeleton Development and progression Genetic aspects Health aspects Human Genetics Humans Hydrogen bonding Internal Medicine Medicine Medicine & Public Health Mice Oncology Oncology, Experimental p21-activated kinase p21-Activated Kinases - chemistry p21-Activated Kinases - genetics p21-Activated Kinases - metabolism Peptide inhibitors Peptides Peptides - chemistry Peptides - metabolism Peptides - pharmacology Phenotypes Phosphorylation Phosphorylation - drug effects Prediction models Protein Binding Protein kinases Protein-serine/threonine kinase Runx3 protein Synthesis Transcription factors Tumor suppressor genes Tumors Xenograft Model Antitumor Assays Xenografts India
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Summary:	P21 Activated Kinase 1 (PAK1) is an oncogenic serine/threonine kinase known to play a significant role in the regulation of cytoskeleton and cell morphology. Runt-related transcription factor 3 (RUNX3) was initially known for its tumor suppressor function, but recent studies have reported the oncogenic role of RUNX3 in various cancers. Previous findings from our laboratory provided evidence that Threonine 209 phosphorylation of RUNX3 acts as a molecular switch in dictating the tissue-specific dualistic functions of RUNX3 for the first time. Based on these proofs and to explore the translational significance of these findings, we designed a small peptide (RMR) from the protein sequence of RUNX3 flanking the Threonine 209 phosphorylation site. The selection of this specific peptide from multiple possible peptides was based on their binding energies, hydrogen bonding, docking efficiency with the active site of PAK1 and their ability to displace PAK1–RUNX3 interaction in our prediction models. We found that this peptide is stable both in in vitro and in vivo conditions, not toxic to normal cells and inhibits the Threonine 209 phosphorylation in RUNX3 by PAK1. We also tested the efficacy of this peptide to block the RUNX3 Threonine 209 phosphorylation mediated tumorigenic functions in in vitro cell culture models, patient-derived explant (PDE) models and in in vivo tumor xenograft models. These results proved that this peptide has the potential to be developed as an efficient therapeutic molecule for targeting RUNX3 Threonine 209 phosphorylation-dependent tumor phenotypes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/s41388-021-01927-x