S100A2 promoter-driven conditionally replicative adenovirus targets non-small-cell lung carcinoma

K. Lee, S. T. Yun, C. O. Yun, Byung-Yoon Ahn, E. C. Jo

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

S100A2, a member of the S100 family of calcium-binding proteins, has been implicated in carcinogenesis as both a tumor suppressor and stimulator. Here, we characterized promoter activity of S100A2, generated an S100A2 promoter-driven conditionally replicative adenovirus (Ad/SA), and evaluated its anti-tumor activity in vitro and in vivo. Promoter activity of S100A2 was greatly restricted to tumor cells, and the S100A2 promoter bound with typical nuclear targets of epidermal growth factor receptor (EGFR) signaling. EGF-stimulated EGFR phosphorylation induced S100A2 expression and further activated E1A expression of Ad/SA, which was restored by EGFR signal inhibition in a concentration-dependent manner in non-small-cell lung carcinoma (NSCLC). In two EGFR-activated tumor xenograft animal models, Ad/SA exhibited potent anti-tumor activity, whereas cetuximab, an EGFR-targeting anticancer drug, was active transiently or ineffective. Combined treatment with cetuximab or cisplatin plus Ad/SA resulted in enhanced anti-tumor activity. Immunohistochemical analysis of tumor sections showed moderate-to-high grade signals for EGFR and adenovirus, and a reduction in viable cells in Ad/SA-treated tumors. Collectively, these results demonstrate that the S100A2 promoter-driven adenovirus is a potent inhibitor of cancers, and further suggest that S100A2 is a target gene of EGFR signaling pathway in NSCLC.

Original languageEnglish
Pages (from-to)967-977
Number of pages11
JournalGene Therapy
Volume19
Issue number10
DOIs
Publication statusPublished - 2012 Oct 1

Fingerprint

Adenoviridae
Non-Small Cell Lung Carcinoma
Epidermal Growth Factor Receptor
Neoplasms
erbB-1 Genes
Calcium-Binding Proteins
Drug Delivery Systems
Epidermal Growth Factor
Heterografts
Cisplatin
Carcinogenesis
Animal Models
Phosphorylation

Keywords

  • Conditionally replicative adenovirus
  • Epidermal growth factor receptor signaling
  • Non-small-cell lung carcinoma
  • S100A2 promoter

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

S100A2 promoter-driven conditionally replicative adenovirus targets non-small-cell lung carcinoma. / Lee, K.; Yun, S. T.; Yun, C. O.; Ahn, Byung-Yoon; Jo, E. C.

In: Gene Therapy, Vol. 19, No. 10, 01.10.2012, p. 967-977.

Research output: Contribution to journalArticle

Lee, K. ; Yun, S. T. ; Yun, C. O. ; Ahn, Byung-Yoon ; Jo, E. C. / S100A2 promoter-driven conditionally replicative adenovirus targets non-small-cell lung carcinoma. In: Gene Therapy. 2012 ; Vol. 19, No. 10. pp. 967-977.
@article{6e64e29078e241a3b573d7af99608d6c,
title = "S100A2 promoter-driven conditionally replicative adenovirus targets non-small-cell lung carcinoma",
abstract = "S100A2, a member of the S100 family of calcium-binding proteins, has been implicated in carcinogenesis as both a tumor suppressor and stimulator. Here, we characterized promoter activity of S100A2, generated an S100A2 promoter-driven conditionally replicative adenovirus (Ad/SA), and evaluated its anti-tumor activity in vitro and in vivo. Promoter activity of S100A2 was greatly restricted to tumor cells, and the S100A2 promoter bound with typical nuclear targets of epidermal growth factor receptor (EGFR) signaling. EGF-stimulated EGFR phosphorylation induced S100A2 expression and further activated E1A expression of Ad/SA, which was restored by EGFR signal inhibition in a concentration-dependent manner in non-small-cell lung carcinoma (NSCLC). In two EGFR-activated tumor xenograft animal models, Ad/SA exhibited potent anti-tumor activity, whereas cetuximab, an EGFR-targeting anticancer drug, was active transiently or ineffective. Combined treatment with cetuximab or cisplatin plus Ad/SA resulted in enhanced anti-tumor activity. Immunohistochemical analysis of tumor sections showed moderate-to-high grade signals for EGFR and adenovirus, and a reduction in viable cells in Ad/SA-treated tumors. Collectively, these results demonstrate that the S100A2 promoter-driven adenovirus is a potent inhibitor of cancers, and further suggest that S100A2 is a target gene of EGFR signaling pathway in NSCLC.",
keywords = "Conditionally replicative adenovirus, Epidermal growth factor receptor signaling, Non-small-cell lung carcinoma, S100A2 promoter",
author = "K. Lee and Yun, {S. T.} and Yun, {C. O.} and Byung-Yoon Ahn and Jo, {E. C.}",
year = "2012",
month = "10",
day = "1",
doi = "10.1038/gt.2011.168",
language = "English",
volume = "19",
pages = "967--977",
journal = "Gene Therapy",
issn = "0969-7128",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - S100A2 promoter-driven conditionally replicative adenovirus targets non-small-cell lung carcinoma

AU - Lee, K.

AU - Yun, S. T.

AU - Yun, C. O.

AU - Ahn, Byung-Yoon

AU - Jo, E. C.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - S100A2, a member of the S100 family of calcium-binding proteins, has been implicated in carcinogenesis as both a tumor suppressor and stimulator. Here, we characterized promoter activity of S100A2, generated an S100A2 promoter-driven conditionally replicative adenovirus (Ad/SA), and evaluated its anti-tumor activity in vitro and in vivo. Promoter activity of S100A2 was greatly restricted to tumor cells, and the S100A2 promoter bound with typical nuclear targets of epidermal growth factor receptor (EGFR) signaling. EGF-stimulated EGFR phosphorylation induced S100A2 expression and further activated E1A expression of Ad/SA, which was restored by EGFR signal inhibition in a concentration-dependent manner in non-small-cell lung carcinoma (NSCLC). In two EGFR-activated tumor xenograft animal models, Ad/SA exhibited potent anti-tumor activity, whereas cetuximab, an EGFR-targeting anticancer drug, was active transiently or ineffective. Combined treatment with cetuximab or cisplatin plus Ad/SA resulted in enhanced anti-tumor activity. Immunohistochemical analysis of tumor sections showed moderate-to-high grade signals for EGFR and adenovirus, and a reduction in viable cells in Ad/SA-treated tumors. Collectively, these results demonstrate that the S100A2 promoter-driven adenovirus is a potent inhibitor of cancers, and further suggest that S100A2 is a target gene of EGFR signaling pathway in NSCLC.

AB - S100A2, a member of the S100 family of calcium-binding proteins, has been implicated in carcinogenesis as both a tumor suppressor and stimulator. Here, we characterized promoter activity of S100A2, generated an S100A2 promoter-driven conditionally replicative adenovirus (Ad/SA), and evaluated its anti-tumor activity in vitro and in vivo. Promoter activity of S100A2 was greatly restricted to tumor cells, and the S100A2 promoter bound with typical nuclear targets of epidermal growth factor receptor (EGFR) signaling. EGF-stimulated EGFR phosphorylation induced S100A2 expression and further activated E1A expression of Ad/SA, which was restored by EGFR signal inhibition in a concentration-dependent manner in non-small-cell lung carcinoma (NSCLC). In two EGFR-activated tumor xenograft animal models, Ad/SA exhibited potent anti-tumor activity, whereas cetuximab, an EGFR-targeting anticancer drug, was active transiently or ineffective. Combined treatment with cetuximab or cisplatin plus Ad/SA resulted in enhanced anti-tumor activity. Immunohistochemical analysis of tumor sections showed moderate-to-high grade signals for EGFR and adenovirus, and a reduction in viable cells in Ad/SA-treated tumors. Collectively, these results demonstrate that the S100A2 promoter-driven adenovirus is a potent inhibitor of cancers, and further suggest that S100A2 is a target gene of EGFR signaling pathway in NSCLC.

KW - Conditionally replicative adenovirus

KW - Epidermal growth factor receptor signaling

KW - Non-small-cell lung carcinoma

KW - S100A2 promoter

UR - http://www.scopus.com/inward/record.url?scp=84867400153&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867400153&partnerID=8YFLogxK

U2 - 10.1038/gt.2011.168

DO - 10.1038/gt.2011.168

M3 - Article

C2 - 22033466

AN - SCOPUS:84867400153

VL - 19

SP - 967

EP - 977

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 10

ER -