Carcinogenesis Advance Access published online on June 4, 2007
Carcinogenesis, doi:10.1093/carcin/bgm133
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Induction of Death Receptor 5 and Suppression of Survivin Contribute to Sensitization of TRAIL-induced cytotoxicity by Quercetin in Non-small Cell Lung Cancer Cells
1 Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute 2425 Ridgecrest Drive SE, Albuquerque, NM 87108, USA
2 West China Second University Hospital, Sichuan University Chengdu 610041, China
Correspondence: Yong Lin, M.D., Ph.D., Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute 2425 Ridgecrest Dr., SE, Albuquerque, NM 87108, Tel: 505-348-9645, Fax: 505-348-4990, E-mail: ylin{at}lrri.org
The natural flavonoid quercetin has been suggested by epidemiological studies to have preventive activity against lung cancer; however, the mechanism of which has not been well elucidated. In this report we demonstrate that quercetin significantly enhances tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells. Quercetin increased expression of death receptor 5 (DR5), whereas it had no effect on that of other components of the death-inducing signaling complex. Conversely, the expression of survivin was potently inhibited by quercetin. We further determined that PKC is essential for DR5 induction but is dispensable for suppression of survivin expression. In contrast, the blockage of Akt activity by quercetin is important for inhibition of survivin expression but not induction of DR5. These results suggest the pathways for regulation of DR5 and survivin expression by quercetin are distinct. Importantly, suppression of survivin-sensitized TRAIL-induced cell death and blockage of DR5 expression suppressed the synergistic cytotoxicity induced by quercetin and TRAIL co-treatment. On the whole, our data show that quercetin sensitizes TRAIL-induced cytotoxicity in lung cancer cells through two independent pathways: induction of DR5 and suppression of survivin expression, which may underlie the mechanism of the lung cancer preventive activity of quercetin. The potentiation of TRAIL-induced NSCLC cell death could be implicated in lung cancer therapy and prevention.
Key Words: TRAIL • apoptosis • survivin • quercetin • lung cancer
Received February 14, 2007; revised April 30, 2007; accepted May 24, 2007.
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