Inhibiting NF-kappaB Activation by Triptolide Enhances TRAIL-induced Cell Death in Lung Cancer Cells.
- Author:
Youn Seup KIM
1
;
Jae Seuk PARK
;
Young Koo JEE
;
Kye Young LEE
Author Information
1. Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea. kyleemd@dankook.ac.kr
- Publication Type:Original Article
- Keywords:
Triptolide;
TRAIL;
NF-kappaB;
Lung cancer;
Apoptosis
- MeSH:
Apoptosis;
Asian Continental Ancestry Group;
Cell Death*;
DNA;
Genes, Reporter;
Hepatocytes;
Homicide;
Humans;
Luciferases;
Lung Neoplasms*;
Lung*;
NF-kappa B*;
Oxygen;
Phenotype;
Shock, Septic;
Transcriptional Activation;
Tripterygium;
Tumor Necrosis Factor-alpha
- From:Journal of Lung Cancer
2003;2(1):61-68
- CountryRepublic of Korea
- Language:English
-
Abstract:
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-alpha and FasL has been hampered by toxic side effects including NF-kappaB 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-kappaB which is a well-known anti-apoptotic transcriptional factor. MATERIALS AND METHODS: We found that TRAIL activates NF-kappaB 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-kappaB 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-kappaB activation. Pretreatment with MG132 which is a well-known NF-kappaB inhibitor by blocking degradation of IkappaBalpha also greatly sensitized lung cancer cells to TRAIL-induced apoptosis. Triptolide did not block DNA binding of NF-kappaB activated by TRAIL as in the case of TNF-alpha. It has been already proven that triptolide blocks transactivation of p65 which plays a key role in NF-kappaB activation. CONCLUSION: These observations suggest that triptolide may be a potentially useful drug to enhance TRAIL-induced tumor killing in lung cancer.
