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KMID : 0982820030020010061
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Journal of Lung Cancer
2003 Volume.2 No. 1 p.61 ~ p.68
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Inhibiting NF-κB Activation by Triptolide Enhances TRAIL-induced Cell Death in Lung Cancer Cells
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Kim Youn-Seup
Park Jae-Seuk
Jee Young-Koo
Lee Kye-Young
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Abstract
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Purpose: High frequency of p53 mutations in lung cancer is a major obstacle to chemotherapy-induced apoptosis because p53 is known to play an important role as a final translator for cancer apoptosis. Members of the TNF family have potential as anti-tumor agents because they induce apoptosis regardless of the p53 phenotype. Despite these advantages, the clinical utility of both TNF-α and FasL has been hampered by toxic side effects including NF-κB activation leading to septic shock and lethal hepatocyte apoptosis respectively. TRAIL (TNF-related apoptosis-inducing ligand), or Apo2L (Apo2 ligand) is a newly identified member of the family which appears to be tumor-selective and less toxic to the normal cells owing to distinct decoy receptor expression. Recently, it was described that TRAIL also can activate NF-κB which is a well-known anti-apoptotic transcriptional factor.
Materials and Methods: We found that TRAIL activates NF-κB in A549 (wt p53) and NCI-H1299 (null p53) lung cancer cells by luciferase reporter gene assay and electromobility shift assay. We set out to identify an agent that would sensitize lung cancer cells to TRAIL-induced apoptosis through inhibition of NF-κB activation.
Results: We found that triptolide, an oxygenated diterpene extracted and purified from the Chinese herb Tripterygium wilfordii sensitized A549 and NCI-H1299 cells to TRAIL-induced apoptosis through inhibition of NF-κB activation. Pretreatment with MG132 which is a well-known NF-κB inhibitor by blocking degradation of IκBα also greatly sensitized lung cancer cells to TRAIL-induced apoptosis. Triptolide did not block DNA binding of NF-κB activated by TRAIL as in the case of TNF-α. It has been already proven that triptolide blocks transactivation of p65 which plays a key role in NF-κB activation.
Conclusion: These observations suggest that triptolide may be a potentially useful drug to enhance TRAIL-induced tumor killing in lung cancer.
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KEYWORD
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Triptolide, TRAIL, NF-κB, Lung cancer, Apoptosis
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