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Extracellular superoxide dismutase (EC-SOD) overexpressionmodulates cellular responses such as tumor cell suppression andis induced by IFNγ. Therefore, we examined the role of EC-SODin IFNγ-mediated tumor cell suppression. We observed that thedominant-negative protein kinase C delta (PKCδ) suppressesIFNγ-induced EC-SOD expression in both keratinocytes andmelanoma cells. Our results also showed that PKCδ-induced ECSODexpression was reduced by pretreatment with a PKCspecificinhibitor or a siRNA against PKCδ. PKCδ-induced ECSODexpression suppressed cell proliferations by the up-regulationof p21 and Rb, and the downregulation of cyclin A and D.Finally, we demonstrated that increased expression of EC-SODdrastically suppressed lung melanoma proliferation in an EC-SODtransgenic mouse via p21 expression. In summary, our findingssuggest that IFNγ-induced EC-SOD expression occurs via activationof PKCδ. Therefore, the upregulation of EC-SOD may beeffective for prevention of various cancers, including melanoma,via cell cycle arrest.