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J. Biol. Chem., Vol. 278, Issue 28, 25490-25498, July 11, 2003

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Inhibition of NF-B Sensitizes A431 Cells to Epidermal Growth Factor-induced Apoptosis, whereas Its Activation by Ectopic Expression of RelA Confers Resistance^*

Ruby John Anto, Manickam Venkatraman  and Devarajan Karunagaran 

From the Division of Cancer Biology, Rajiv Gandhi Center for Biotechnology, Thiruvananthapuram, Kerala-695014, India

Epidermal growth factor (EGF) is a well known mitogen, but it paradoxically induces apoptosis in cells that overexpress its receptor. We demonstrate for the first time that the EGF-induced apoptosis is accelerated if NF-B is inactivated. To inactivate NF-B, human epidermoid carcinoma cells (A431) that overexpress EGF receptor were stably transfected with an IB- double mutant construct. Under the NF-B-inactivated condition, A431 cells were more sensitive to EGF with decreased cell viability and increased externalization of phosphatidylserine on the cell surface, DNA fragmentation, and activation of caspases (3 and 8 but not 9), typical features of apoptosis. These results were further supported by the potentiation of the growth inhibitory effects of EGF by chemical inhibitors of NF-B (curcumin and sodium salicylate) and the protective role of RelA evidenced by the resistance of A431-RelA cells (stably transfected with RelA) to EGF-induced apoptosis. EGF treatment or ectopic expression of RelA in A431 cells induced DNA binding activity of NF-B (p50 and RelA) and the expression of c-IAP1, a downstream target of NF-B. A431-RelA cells exhibited spontaneous phosphorylation of Akt (a downstream target of phosphatidylinositol 3-kinase and regulator of NF-B) and EGF treatment stimulated it further. Blocking this basal Akt phosphorylation with LY294002, an inhibitor of phosphatidylinositol 3-kinase, did not affect their viability but blocking of EGF-induced phosphorylation of Akt sensitized the otherwise resistant A431-RelA cells to EGF-mediated growth inhibition. Our results favor an anti-apoptotic role for NF-B in the regulation of EGF-induced apoptosis.

Received for publication, February 19, 2003 , and in revised form, April 16, 2003.

^* This work was supported in part by grants from the Department of Science and Technology, Government of India and the Science, Technology and Environment committee, Government of Kerala, India (to D. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Senior Research Fellowship from the Council of Scientific and Industrial Research, India.

To whom correspondence should be addressed. Tel.: 91-471-2347975; Fax: 91-471-2348096; E-mail: dkarunagaran{at}hotmail.com.

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