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 language | English |
|---|---|
| Pages (from-to) | 967-977 |
| Number of pages | 11 |
| Journal | Gene Therapy |
| Volume | 19 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2012 Oct 1 |
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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 journal › Article
}
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 -