Journal
CANCER LETTERS
Volume 307, Issue 2, Pages 227-236Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2011.04.008
Keywords
Epidermal growth factor receptor (EGFR); NR4A2; PGE(2); Resistance to anti-cancer drug; Squamous cell carcinoma
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Grants-in-Aid for Scientific Research [23592734, 23592963, 10J06035] Funding Source: KAKEN
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We found a linear correlation between the Prostaglandin E-2 (PGE(2)) amount and the NR4A2 expression in oral squamous cell carcinoma (SCC) tissues through a statistical analysis among 41 clinical cases. In SCC cell lines, PGE(2) receptor (EP) ligation by exogenous PGE(2) promoted the NR4A2 expression in the cAMP/protein kinase A (PKA)-dependent manner. The process required a nature of SCC cell represented by constitutive activated epidermal growth factor receptor (EGFR) family. Targeted inactivation of the EGFRs interfered the PGE(2)-dependent NR4A2 expression. The PGE(2)-dependent NR4A2 induction is essential for the resistance to anti-cancer drug-induced apoptosis especially in SCC cells which showed constitutive EGFRs activity via autocrine epiregulin, a ligand for EGFRs. Conversely, SCC cells which lack epiregulin expression in their nature could gain the ability to promote the NR4A2 expression in response to PGE(2) and attain the resistance to anti-cancer drug-induced apoptosis under the existence of exogenous epiregulin. These findings suggest that susceptibility of SCC to anti-cancer drug could be compromised when PGE(2) was delivered in the microenvironment of SCC cells supported by constitutive EGFR family activities as their nature. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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