Nuclear and cytoplasmic death receptor 5 as prognostic factors in patients with non-small cell lung cancer treated with chemotherapy.
BACKGROUND
Death receptor 4 (DR4) and death receptor 5 (DR5) are tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) receptors that activate apoptosis via the extrinsic apoptosis pathway. DcR1 and DcR2 are decoy receptors for TRAIL that act antagonistically. Intracellular trafficking of TRAIL receptors has been described, but the role of the subcellular localization of TRAIL receptors in non-small cell lung cancer (NSCLC) progression is unclear.


METHODS
Expression and intracellular localization of pro-apoptotic and decoy TRAIL receptors were analyzed by immunohistochemistry in 50 samples of advanced or recurrent NSCLC. Using confocal microscopy, localization of TRAIL receptors was studied in NSCLC cell lines.


RESULTS
Cytoplasmic staining for all four TRAIL receptors was observed in the majority of samples. Nuclear staining was infrequent in the case of DR4 (12%) and DcR2 (8%), while DR5 and DcR1 were localized in the nucleus in 27% and 60% of samples. When overall survival was analyzed, cytoplasmic staining for DR5 in tumor cells (P=0.025) and nuclear staining for DR5 in tumor cells (P=0.007) were significant prognostic factors in univariate, as well as in multivariate analysis including clinicopathologic factors (P=0.026 and 0.021, respectively). In A549, NCI-H358, and A427 NSCLC cells all four TRAIL receptors were found to be mainly located perinuclearly, but also in the nucleus.


CONCLUSIONS
The study for the first time shows that TRAIL receptors are found in different intracellular compartments including the nucleus in NSCLC cells and that both nuclear and cytoplasmic DR5 might predict improved survival in patients with advanced NSCLC.
Leithner
Katharina
K
Department of Pulmonology, University Clinic of Internal Medicine, Lung Cell Laboratory, Medical University of Graz, Auenbruggerplatz 20, Graz A-8036, Austria.
Stacher
Elvira
E
Wurm
Robert
R
Ploner
Ferdinand
F
Quehenberger
Franz
F
Wohlkoenig
Christoph
C
Bálint
Zoltán
Z
Polachova
Jana
J
Olschewski
Andrea
A
Samonigg
Hellmut
H
Popper
Helmut H
HH
Olschewski
Horst
H
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
D014408:Biomarkers, Tumor; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand