Abstract A63: Superoxide-dependent MKP-1 degradation and JNK activation contribute to luteolin-induced cytotoxicity in lung cancer cells

Abstract

Abstract Epidemiological studies have suggested luteolin (3′,4′,5,7-tetrahydroxyflavone) as a potential cancer preventive agent. Recently we found that luteolin selectively kills lung cancer but not immortalized human normal bronchial epithelial cells (HBECs). To elucidate the mechanism of luteolin's cancer cell killing activity, we used an in vitro cell culture system to investigate the cytotoxic cellular signaling pathway in lung cancer cells. The results show that luteolin potently induced both apoptosis and necrosis, which was associated with mitochondrion-dependent superoxide accumulation in lung cancer cells. The c-Jun N-terminal kinase (JNK) was substantially activated in luteolin treated cancer cells and luteolin-induced cytotoxicity was effectively blocked when JNK was inhibited. The reactive oxygen species scavengers BHA and NAC, which effectively block luteolin-induced superoxide accumulation, potently suppressed luteolin-induced JNK activation and cytotoxicity, suggesting that luteolin's lung cancer cell killing requires superoxide-mediated JNK activation. Furthermore, JNK activation was tightly associated with a superoxide-dependent rapid reduction of the JNK inactivating phosphatase MKP-1, which was mainly due to destabilizing MKP-1 protein. These results suggest that inhibiting MKP-1 is the main mechanism for luteolin-induced JNK activation. Thus, luteolin activates a novel cytotoxic pathway consisting of superoxide, MKP-1 and JNK in lung cancer cells. Interestingly, although luteolin-induced superoxide accumulation was comparable to that in lung cancer cells, it failed in inducing JNK activation and cell death in the HBECs. Therefore, luteolin-induced cellular signaling in normal and lung cancer cells diverges at the step of JNK activation. Taken together, our results suggest that activation of the speroxide/MKP1/JNK pathway underlies the main mechanism of luteolin's selective ctyotoxicity in lung cancer cells and manipulation of this pathway could be a useful approach for applying luteolin for lung cancer prevention and therapy. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A63.