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PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2
- Source :
- Oncogene. 22:5427-5435
- Publication Year :
- 2003
- Publisher :
- Springer Science and Business Media LLC, 2003.
-
Abstract
- Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to the family of programmed cell death-inducing cytokines. Apo2L/TRAIL induces apoptosis in a wide variety of tumor cells. Tumor cells that are resistant to Apo2L/TRAIL-induced apoptosis can be sensitized by chemotherapeutic drugs and other agents via an unknown mechanism. Here we report that PG490 (triptolide), a diterpene triepoxide extracted from the Chinese herb Tripterygium wilfordii and used in traditional Chinese medicine, sensitizes lung cancer but not normal human bronchial epithelial cells to Apo2L/TRAIL-induced apoptosis. Sensitization was accompanied by caspase-3 and caspase-8 activation, whereas no cleavage of caspase-9 was observed. Determination of cell surface receptors by flow cytometry demonstrated no difference in Apo2L/TRAIL-R1 and -R2 expression, the two receptors with functional death domains, between resistant and sensitized cells. In cells treated with the combination of Apo2L/TRAIL and PG490, we observed activation of ERK2, a member of the mitogen-activated protein kinase family. Furthermore, sensitization could be blocked by the ERK inhibitor U0126 but not the p38 inhibitor SB203580, suggesting that activation of ERK2 is required for this effect. In addition, sensitization of lung cancer cells was also seen in ex vivo culture of lung cancer tissue from four patients who underwent surgery. Immunohistochemical staining showed a clear reduction in proliferation cell nuclear antigen (PCNA) in tissue treated with Apo2L/TRAIL and PG490. In conclusion, apoptosis induced by the combination of Apo2L/TRAIL and PG490 warrants further evaluation as a potential new strategy for the treatment of lung cancer.
- Subjects :
- Cancer Research
Lung Neoplasms
p38 mitogen-activated protein kinases
Cell
Apoptosis
Biology
TNF-Related Apoptosis-Inducing Ligand
chemistry.chemical_compound
Genetics
medicine
Humans
Receptor
Lung cancer
Antineoplastic Agents, Alkylating
Molecular Biology
Sensitization
Mitogen-Activated Protein Kinase 1
Membrane Glycoproteins
Tumor Necrosis Factor-alpha
Phenanthrenes
Triptolide
medicine.disease
Enzyme Activation
medicine.anatomical_structure
chemistry
Immunology
Cancer research
Epoxy Compounds
Tumor necrosis factor alpha
Diterpenes
Apoptosis Regulatory Proteins
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....eaaafa8d6f082930fdd57708ef58beb5