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First published on February 12, 2007; DOI: 10.1124/mol.106.032185

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Received for publication October 25, 2006.
Revised January 18, 2007.
Accepted for publication February 12, 2007.

A CRITICAL ROLE OF LUTEOLIN-INDUCED REACTIVE OXYGEN SPECIES IN BLOCKAGE OF TUMOR NECROSIS FACTOR-ACTIVATED NUCLEAR FACTOR-{kappa}B PATHWAY AND SENSITIZATION OF APOPTOSIS IN LUNG CANCER CELLS

Wei Ju 1, Xia Wang 1, Wenshu Chen 1, Honglian Shi 2, Steven A. Belinsky 1, Yong Lin 1*

1 Lovelace Respiratory Research Institute 2 University of New Mexico

* Address correspondence to: E-mail: ylin{at}lrri.org

Abstract

Nuclear factor {kappa}B (NF-{kappa}B) activated by tumor necrosis factor (TNF) attenuates the TNF-induced apoptosis pathway. Therefore, blockage of NF-{kappa}B should improve the anti-cancer activity of TNF. Luteolin, a naturally occurring polyphenol flavonoid, has been reported to sensitize colorectal cancer cells to TNF-induced apoptosis through suppression of NF-{kappa}B; however, the mechanisms of this effect have not been well elucidated. In this paper, we provide evidence showing a critical role of reactive oxygen species (ROS) accumulation induced by luteolin in modulating TNF-activated pathways in lung cancer cells. Luteolin effectively suppressed NF-{kappa}B while potentiated the c-Jun N-terminal kinase (JNK) to increase apoptosis induced by TNF in lung cancer cells. Our results further demonstrate that luteolin induced an early-phase ROS accumulation via suppression of the cellular superoxide dismutase activity. Importantly, suppression of ROS accumulation by ROS scavengers butylated hydroxyanisole and N-acetyl-L-cysteine prevented the luteolin-induced suppression of NF-{kappa}B and potentiation of JNK, and significantly suppressed the synergistic cytotoxicity seen with co-treatment of luteolin and TNF. Taken together, these results suggest that the accumulation of ROS induced by luteolin plays a pivotal role in suppression of NF-{kappa}B and potentiation of JNK to sensitize lung cancer cells to undergo TNF-induced apoptosis.


Key words: Tumor necrosis factor, NFkappaB, Apoptosis, Oxidative stress/antioxidants


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