Abstract
Although luteolin is implicated as a potential cancer therapeutic and preventive agent due to its potent cancer cell killing activity, the molecular mechanisms by which luteolin’s cancer cell cytotoxicity is achieved have not been well elucidated. In this report, the 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 non-apoptotic death in lung cancer cells. The c-Jun N-terminal kinase (JNK) was potently activated following 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 MKK7, the latter was not dependent on superoxide. We further found that luteolin triggers a superoxide-dependent rapid degradation of the JNK inactivating phosphatase MKP-1. Introduction of a degradation-resistant MKP-1 mutant effectively attenuated luteolin-induced JNK activation and cytotoxicity, suggesting that inhibiting the JNK suppressor MKP-1 plays a major role in luteolin-induced lung cancer cell death. Collectively, our results unveil a novel pathway consisting of superoxide, MKP1 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.
- Received November 2, 2011.
- Revision received January 4, 2012.
- Accepted January 5, 2012.
- The American Society for Pharmacology and Experimental Therapeutics