Inhibition of cancer cell proliferation by designed peptide amphiphiles.
HOX genes encode conserved transcription factors that control the morphological diversification along the anteroposterior body axis. HOX proteins bind to DNA through a highly conserved 60 amino acid sequence called the homeodomain, and greater DNA binding specificity and stability are achieved when it forms complexes with cofactors such as PBX and MEIS in humans. In particular, HOX proteins from paralog groups 1-8, interact with PBX proteins via a specific and highly conserved hydrophobic six amino acid sequence localized in the N-terminal region of HOX. In several oncogenic transformations, deregulated HOX gene expression has been observed, indicating an involvement of these transcriptional regulators in carcinogenesis and metastasis. Inhibition of the HOX-PBX interaction could be a strategy to control the abnormal proliferation of these cancer cells. In this study we describe a small designed peptide amphiphile (PA) which self-assembles into micelles and shows inhibition of T3M4 pancreatic cancer cells, K562 leukemia cells and MJT1 melanoma cells while non-cancerous fibroblast NIH 3T3 cells are less affected. This molecule contains three critical regions: a 9-amino-acid sequence designed to disrupt HOX/PBX/DNA complex formation, a 16-amino-acid sequence to deliver the peptide into the cell and a 16-carbon-acyl chain which we show leads to the molecule's self-assembly and significantly enhances the effectiveness of the molecule to slow cell proliferation.
Aulisa
Lorenzo
L
Department of Chemistry, Rice University, Houston, TX 77005, USA.
Forraz
Nico
N
McGuckin
Colin
C
Hartgerink
Jeffrey D
JD
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020014:K562 Cells; D008545:Melanoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008823:Micelles; D008969:Molecular Sequence Data; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D008823:Micelles; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D010455:Peptides; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; C083400:PBX1 protein, human; D004247:DNA