Disrupting Skp2-cylin A interaction with a blocking peptide induces selective cancer cell killing

Peng Ji, Daqian Sun, Hongbo Wang, Frederick Bauzon, Liang Zhu

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Skp2 fulfills the definition of an oncoprotein with its frequent overexpression in cancer cells and oncogenic activity in various laboratory assays and therefore is a potential cancer therapy target. The best-known function of Skp2 is that of an F-box protein of the SCFSkp2-Roc1 E3 ubiquitin ligase targeting the cyclin-dependent kinase inhibitor P27Kip1. Knockdown of Skp2 generally leads to accumulation of p27 but its effects on cancer cells are less certain. Another function of Skp2 is its stable interaction with cyclin A, which directly protects cyclin A from inhibition by p27 in in vitro kinase assays. Here, we report that an 18-residue blocking peptide of Skp2-cyclin A interaction can indirectly inhibit cyclin A/Cdk2 kinase activity dependent on the presence of p27 in in vitro kinase assays. Transmembrane delivery of this blocking peptide can induce cell death in a panel of four cancer cell lines in which Skp2 knockdown only have mild inhibitory effects. This Skp2-cyclin A interaction blocking peptide can synergize with a previously identified E2F1-derived LDL peptide, which blocks its access to cyclin A, in killing cancer cells. IC50 of the Skp2-cyclin A blocking peptide correlated with abundance of Skp2, its intended target, in cancer cells. These results suggest that Skp2-cyclin A interaction plays an important role in cancer cell survival and is an attractive target for cancer drug discovery.

Original languageEnglish (US)
Pages (from-to)684-691
Number of pages8
JournalMolecular Cancer Therapeutics
Volume6
Issue number2
DOIs
StatePublished - Feb 2007

Fingerprint

Cyclin A
Peptides
Neoplasms
Phosphotransferases
F-Box Proteins
Ubiquitin-Protein Ligases
Cyclin-Dependent Kinases
Oncogene Proteins
Drug Discovery
Inhibitory Concentration 50
Cell Survival
Cell Death
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Disrupting Skp2-cylin A interaction with a blocking peptide induces selective cancer cell killing. / Ji, Peng; Sun, Daqian; Wang, Hongbo; Bauzon, Frederick; Zhu, Liang.

In: Molecular Cancer Therapeutics, Vol. 6, No. 2, 02.2007, p. 684-691.

Research output: Contribution to journalArticle

@article{282a8c6d4f2a479589527de3b74b47c6,
title = "Disrupting Skp2-cylin A interaction with a blocking peptide induces selective cancer cell killing",
abstract = "Skp2 fulfills the definition of an oncoprotein with its frequent overexpression in cancer cells and oncogenic activity in various laboratory assays and therefore is a potential cancer therapy target. The best-known function of Skp2 is that of an F-box protein of the SCFSkp2-Roc1 E3 ubiquitin ligase targeting the cyclin-dependent kinase inhibitor P27Kip1. Knockdown of Skp2 generally leads to accumulation of p27 but its effects on cancer cells are less certain. Another function of Skp2 is its stable interaction with cyclin A, which directly protects cyclin A from inhibition by p27 in in vitro kinase assays. Here, we report that an 18-residue blocking peptide of Skp2-cyclin A interaction can indirectly inhibit cyclin A/Cdk2 kinase activity dependent on the presence of p27 in in vitro kinase assays. Transmembrane delivery of this blocking peptide can induce cell death in a panel of four cancer cell lines in which Skp2 knockdown only have mild inhibitory effects. This Skp2-cyclin A interaction blocking peptide can synergize with a previously identified E2F1-derived LDL peptide, which blocks its access to cyclin A, in killing cancer cells. IC50 of the Skp2-cyclin A blocking peptide correlated with abundance of Skp2, its intended target, in cancer cells. These results suggest that Skp2-cyclin A interaction plays an important role in cancer cell survival and is an attractive target for cancer drug discovery.",
author = "Peng Ji and Daqian Sun and Hongbo Wang and Frederick Bauzon and Liang Zhu",
year = "2007",
month = "2",
doi = "10.1158/1535-7163.MCT-06-0538",
language = "English (US)",
volume = "6",
pages = "684--691",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Disrupting Skp2-cylin A interaction with a blocking peptide induces selective cancer cell killing

AU - Ji, Peng

AU - Sun, Daqian

AU - Wang, Hongbo

AU - Bauzon, Frederick

AU - Zhu, Liang

PY - 2007/2

Y1 - 2007/2

N2 - Skp2 fulfills the definition of an oncoprotein with its frequent overexpression in cancer cells and oncogenic activity in various laboratory assays and therefore is a potential cancer therapy target. The best-known function of Skp2 is that of an F-box protein of the SCFSkp2-Roc1 E3 ubiquitin ligase targeting the cyclin-dependent kinase inhibitor P27Kip1. Knockdown of Skp2 generally leads to accumulation of p27 but its effects on cancer cells are less certain. Another function of Skp2 is its stable interaction with cyclin A, which directly protects cyclin A from inhibition by p27 in in vitro kinase assays. Here, we report that an 18-residue blocking peptide of Skp2-cyclin A interaction can indirectly inhibit cyclin A/Cdk2 kinase activity dependent on the presence of p27 in in vitro kinase assays. Transmembrane delivery of this blocking peptide can induce cell death in a panel of four cancer cell lines in which Skp2 knockdown only have mild inhibitory effects. This Skp2-cyclin A interaction blocking peptide can synergize with a previously identified E2F1-derived LDL peptide, which blocks its access to cyclin A, in killing cancer cells. IC50 of the Skp2-cyclin A blocking peptide correlated with abundance of Skp2, its intended target, in cancer cells. These results suggest that Skp2-cyclin A interaction plays an important role in cancer cell survival and is an attractive target for cancer drug discovery.

AB - Skp2 fulfills the definition of an oncoprotein with its frequent overexpression in cancer cells and oncogenic activity in various laboratory assays and therefore is a potential cancer therapy target. The best-known function of Skp2 is that of an F-box protein of the SCFSkp2-Roc1 E3 ubiquitin ligase targeting the cyclin-dependent kinase inhibitor P27Kip1. Knockdown of Skp2 generally leads to accumulation of p27 but its effects on cancer cells are less certain. Another function of Skp2 is its stable interaction with cyclin A, which directly protects cyclin A from inhibition by p27 in in vitro kinase assays. Here, we report that an 18-residue blocking peptide of Skp2-cyclin A interaction can indirectly inhibit cyclin A/Cdk2 kinase activity dependent on the presence of p27 in in vitro kinase assays. Transmembrane delivery of this blocking peptide can induce cell death in a panel of four cancer cell lines in which Skp2 knockdown only have mild inhibitory effects. This Skp2-cyclin A interaction blocking peptide can synergize with a previously identified E2F1-derived LDL peptide, which blocks its access to cyclin A, in killing cancer cells. IC50 of the Skp2-cyclin A blocking peptide correlated with abundance of Skp2, its intended target, in cancer cells. These results suggest that Skp2-cyclin A interaction plays an important role in cancer cell survival and is an attractive target for cancer drug discovery.

UR - http://www.scopus.com/inward/record.url?scp=33847387601&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847387601&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-06-0538

DO - 10.1158/1535-7163.MCT-06-0538

M3 - Article

VL - 6

SP - 684

EP - 691

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 2

ER -