TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis
Niklas Finnberg, … , Andres J.P. Klein-Szanto, Wafik S. El-Deiry
Niklas Finnberg, … , Andres J.P. Klein-Szanto, Wafik S. El-Deiry
Published December 13, 2007
Citation Information: J Clin Invest. 2008;118(1):111-123. https://doi.org/10.1172/JCI29900.
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TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis

Abstract

Preclinical data support the potential of the death-signaling receptors for TRAIL as targets for cancer therapy. However, it is unclear whether these death-signaling receptors suppress the emergence and growth of malignant tumors in vivo. Herein we show that TNF-related apoptosis-inducing ligand receptor (TRAIL-R), the only proapoptotic death-signaling receptor for TRAIL in the mouse, suppresses inflammation and tumorigenesis. Loss of a single TRAIL-R allele on the lymphoma-prone Eμ-myc genetic background significantly reduced median lymphoma-free survival. TRAIL-R–deficient lymphomas developed with equal frequency irrespective of mono- or biallelic loss of TRAIL-R, had increased metastatic potential, and showed apoptotic defects relative to WT littermates. In addition, TRAIL-R–/– mice showed decreased long-term survival following a sublethal dose of ionizing radiation. Histological evaluation of moribund irradiated TRAIL-R–/– animals showed hallmarks of bronchopneumonia as well as tumor formation with increased NF-κB p65 expression. TRAIL-R also suppressed diethylnitrosamine-induced (DEN-induced) hepatocarcinogenesis, as an increased number of large tumors with apoptotic defects developed in the livers of DEN-treated TRAIL-R–/– mice. Thus TRAIL-R may function as an inflammation and tumor suppressor in multiple tissues in vivo.

Authors

Niklas Finnberg, Andres J.P. Klein-Szanto, Wafik S. El-Deiry

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Figure 3

WT Eμ-myc lymphomas are resistant to TRAIL in vitro and express high levels of FLIPs.

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WT Eμ-myc lymphomas are resistant to TRAIL in vitro and express high le...
(A) Challenging isolated WT Eμ-myc lymphoma cells in vitro with TRAIL resulted in lack of cell death (as determined by tryphan blue staining) in comparison with treatment with etoposide. (B) In vitro cell death assays. Propidium iodide uptake (red staining) and fluorescent-labeled inhibitor of caspase activity (FLICA or FITC-VAD-FMK; green staining) suggest that TRAIL (1 μg/ml) only weakly triggers caspase activity and cell death relative to control in comparison with treatment with etoposide (1 μM) in living Eμ-myc lymphoma cells. (C) Total RNA isolated from WT western blot of splenic and thymic lymphomas shows increased expression of c-FLIPS in WT relative to TRAIL-R+/– lymphomas. (D) Densitometric analysis using NIH ImageJ of western blots from lymphomas (splenic and thymic) from WT (n = 10) and TRAIL-R+/– (n = 10) mice. The ratios of the FLIPs band in relation to the actin band (loading control) is shown. The red horizontal band represents median, and the red cross represents the mean. WT lymphomas have a higher FLIPs/actin ratio (P < 0.05, Student’s t test), suggesting a relatively higher FLIPs expression compared with TRAIL-R+/– lymphomas.