TY - JOUR T1 - A Superoxide-Mediated Mitogen-Activated Protein Kinase Phosphatase-1 Degradation and c-Jun NH<sub>2</sub>-Terminal Kinase Activation Pathway for Luteolin-Induced Lung Cancer Cytotoxicity JF - Molecular Pharmacology JO - Mol Pharmacol SP - 549 LP - 555 DO - 10.1124/mol.111.076653 VL - 81 IS - 4 AU - Lang Bai AU - Xiuling Xu AU - Qiong Wang AU - Shanling Xu AU - Wei Ju AU - Xia Wang AU - Wenshu Chen AU - Weiyang He AU - Hong Tang AU - Yong Lin Y1 - 2012/04/01 UR - http://molpharm.aspetjournals.org/content/81/4/549.abstract N2 - Although luteolin is identified as a potential cancer therapeutic and preventive agent because of its potent cancer cell-killing activity, the molecular mechanisms by which its cancer cell cytotoxicity is achieved have not been well elucidated. In this report, luteolin-induced cellular signaling was systematically investigated, and a novel pathway for luteolin's lung cancer killing was identified. The results show that induction of superoxide is an early and crucial step for luteolin-induced apoptotic and nonapoptotic death in lung cancer cells. The c-Jun N-terminal kinase (JNK) was potently activated after superoxide accumulation. Suppression of superoxide completely blocked luteolin-induced JNK activation, which was well correlated to alleviation of luteolin's cytotoxicity. Although luteolin slightly stimulated the JNK-activating kinase mitogen-activated protein kinase kinase 7, the latter was not dependent on superoxide. We further found that luteolin triggers a superoxide-dependent rapid degradation of the JNK-inactivating phosphatase mitogen-activated protein kinase phosphatase-1 (MKP-1). Introduction of a degradation-resistant MKP-1 mutant effectively attenuated luteolin-induced JNK activation and cytotoxicity, suggesting that inhibition of the JNK suppressor MKP-1 plays a major role in luteolin-induced lung cancer cell death. Taken together, our results unveil a novel pathway consisting of superoxide, MKP-1, and JNK for luteolin's cytotoxicity in lung cancer cells, and manipulation of this pathway could be a useful approach for applying luteolin for lung cancer prevention and therapy. ER -