A superoxide-mediated mitogen-activated protein kinase phosphatase-1 degradation and c-Jun NH(2)-terminal kinase activation pathway for luteolin-induced lung cancer cytotoxicity.
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.
Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
Lang
L
Bai
Xiuling
X
Xu
Qiong
Q
Wang
Shanling
S
Xu
Wei
W
Ju
Xia
X
Wang
Wenshu
W
Chen
Weiyang
W
He
Hong
H
Tang
Yong
Y
Lin
D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D047311:Luteolin / Q000633:toxicity*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism*
D017931:DNA Primers; D013481:Superoxides; D054638:Dual Specificity Phosphatase 1; D046988:Proteasome Endopeptidase Complex; D047311:Luteolin