Inhibition of tissue transglutaminase sensitizes TRAIL-resistant lung cancer cells through upregulation of death receptor 5.
Tissue transglutaminase (TG2) is implicated in cellular processes such as apoptosis and cell migration. Its acyl transferase activity cross-links certain proteins, among them transcription factors were described. We show here that the TG2 inhibitor KCC009 reversed resistance to tumor necrosis factor-related apoptosis-inducing factor (TRAIL) in lung cancer cells. Sensitization required upregulation of death receptor 5 (DR5) but not of death receptor 4. Upregulation of DR5 involved the first intron of the DR5 gene albeit it was independent from p53 and nuclear factor kappa B. In conclusion, inhibition of tissue transglutaminase provides an interesting strategy for sensitization to TRAIL-induced apoptosis in p53-deficient lung cancer cells.
Frese-Schaper
Manuela
M
Department of Clinical Research, University of Bern, Bern, Switzerland.
Schardt
Julian A
JA
Sakai
Toshiyuki
T
Carboni
Giovanni L
GL
Schmid
Ralph A
RA
Frese
Steffen
S
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D019204:GTP-Binding Proteins; D006801:Humans; D015151:Immunoblotting; D007438:Introns / Q000235:genetics; D007555:Isoxazoles / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy*; D011401:Promoter Regions, Genetic / Q000235:genetics; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*; D011503:Transglutaminases / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000187:drug effects
D007555:Isoxazoles; C510621:KCC 009; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins