Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability.
The Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor that is activated by phosphorylation at S102 whereby it induces the expression of growth promoting genes such as EGFR and HER-2. We recently illustrated by an in vitro kinase assay that a novel peptide to YB-1 was hi...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-09-01
|
| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20844753/?tool=EBI |
| _version_ | 1811258288479666176 |
|---|---|
| author | Jennifer H Law Yvonne Li Karen To Michelle Wang Arezoo Astanehe Karen Lambie Jaspreet Dhillon Steven J M Jones Martin E Gleave Connie J Eaves Sandra E Dunn |
| author_facet | Jennifer H Law Yvonne Li Karen To Michelle Wang Arezoo Astanehe Karen Lambie Jaspreet Dhillon Steven J M Jones Martin E Gleave Connie J Eaves Sandra E Dunn |
| author_sort | Jennifer H Law |
| collection | DOAJ |
| description | The Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor that is activated by phosphorylation at S102 whereby it induces the expression of growth promoting genes such as EGFR and HER-2. We recently illustrated by an in vitro kinase assay that a novel peptide to YB-1 was highly phosphorylated by the serine/threonine p90 S6 kinases RSK-1 and RSK-2, and to a lesser degree PKCα and AKT. Herein, we sought to develop this decoy cell permeable peptide (CPP) as a cancer therapeutic. This 9-mer was designed as an interference peptide that would prevent endogenous YB-1(S102) phosphorylation based on molecular docking. In cancer cells, the CPP blocked P-YB-1(S102) and down-regulated both HER-2 and EGFR transcript level and protein expression. Further, the CPP prevented YB-1 from binding to the EGFR promoter in a gel shift assay. Notably, the growth of breast (SUM149, MDA-MB-453, AU565) and prostate (PC3, LNCap) cancer cells was inhibited by ∼90% with the CPP. Further, treatment with this peptide enhanced sensitivity and overcame resistance to trastuzumab in cells expressing amplified HER-2. By contrast, the CPP had no inhibitory effect on the growth of normal immortalized breast epithelial (184htert) cells, primary breast epithelial cells, nor did it inhibit differentiation of hematopoietic progenitors. These data collectively suggest that the CPP is a novel approach to suppressing the growth of cancer cells while sparing normal cells and thereby establishes a proof-of-concept that blocking YB-1 activation is a new course of cancer therapeutics. |
| first_indexed | 2024-04-12T18:10:53Z |
| format | Article |
| id | doaj.art-3147afe5871e4fafa2b7c7e078bf833e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T18:10:53Z |
| publishDate | 2010-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3147afe5871e4fafa2b7c7e078bf833e2022-12-22T03:21:49ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-09-0159e1266110.1371/journal.pone.0012661Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. Jennifer H LawYvonne LiKaren ToMichelle WangArezoo AstaneheKaren LambieJaspreet DhillonSteven J M JonesMartin E GleaveConnie J EavesSandra E DunnThe Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor that is activated by phosphorylation at S102 whereby it induces the expression of growth promoting genes such as EGFR and HER-2. We recently illustrated by an in vitro kinase assay that a novel peptide to YB-1 was highly phosphorylated by the serine/threonine p90 S6 kinases RSK-1 and RSK-2, and to a lesser degree PKCα and AKT. Herein, we sought to develop this decoy cell permeable peptide (CPP) as a cancer therapeutic. This 9-mer was designed as an interference peptide that would prevent endogenous YB-1(S102) phosphorylation based on molecular docking. In cancer cells, the CPP blocked P-YB-1(S102) and down-regulated both HER-2 and EGFR transcript level and protein expression. Further, the CPP prevented YB-1 from binding to the EGFR promoter in a gel shift assay. Notably, the growth of breast (SUM149, MDA-MB-453, AU565) and prostate (PC3, LNCap) cancer cells was inhibited by ∼90% with the CPP. Further, treatment with this peptide enhanced sensitivity and overcame resistance to trastuzumab in cells expressing amplified HER-2. By contrast, the CPP had no inhibitory effect on the growth of normal immortalized breast epithelial (184htert) cells, primary breast epithelial cells, nor did it inhibit differentiation of hematopoietic progenitors. These data collectively suggest that the CPP is a novel approach to suppressing the growth of cancer cells while sparing normal cells and thereby establishes a proof-of-concept that blocking YB-1 activation is a new course of cancer therapeutics.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20844753/?tool=EBI |
| spellingShingle | Jennifer H Law Yvonne Li Karen To Michelle Wang Arezoo Astanehe Karen Lambie Jaspreet Dhillon Steven J M Jones Martin E Gleave Connie J Eaves Sandra E Dunn Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. PLoS ONE |
| title | Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. |
| title_full | Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. |
| title_fullStr | Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. |
| title_full_unstemmed | Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. |
| title_short | Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. |
| title_sort | molecular decoy to the y box binding protein 1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20844753/?tool=EBI |
| work_keys_str_mv | AT jenniferhlaw moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT yvonneli moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT karento moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT michellewang moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT arezooastanehe moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT karenlambie moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT jaspreetdhillon moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT stevenjmjones moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT martinegleave moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT conniejeaves moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability AT sandraedunn moleculardecoytotheyboxbindingprotein1suppressesthegrowthofbreastandprostatecancercellswhilstsparingnormalcellviability |