title: PG490-mediated sensitization of lung cancer cells to Apo2L/TRAIL-induced apoptosis requires activation of ERK2.
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.
authors.affiliation: Department of Clinical Research, Division of General Thoracic Surgery, University Hospital Berne, Switzerland. steffen.frese@email.de
authors.forename: Steffen
authors.initials: S
authors.lastname: Frese
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Pirnia
authors.forename: Daniela
authors.initials: D
authors.lastname: Miescher
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Markus M
authors.initials: MM
authors.lastname: Borner
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Schmid
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D004224:Diterpenes / Q000494:pharmacology; D004789:Enzyme Activation; D004852:Epoxy Compounds; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D010616:Phenanthrenes; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D051017:Apoptosis Regulatory Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; D008562:Membrane Glycoproteins; D010616:Phenanthrenes; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C001899:triptolide; D019950:Mitogen-Activated Protein Kinase 1