TRAIL receptor signaling regulation of chemosensitivity in vivo but not in vitro.
BACKGROUND
Signaling by Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) and Fas ligand (FasL) has been proposed to contribute to the chemosensitivity of tumor cells treated with various other anti-cancer agents. However, the importance of these effects and whether there are differences in vitro and in vivo is unclear.


RESULTS
To assess the relative contribution of death receptor pathways to this sensitivity and to determine whether these effects are intrinsic to the tumor cells, we compared the chemosensitivity of isogenic BJAB human lymphoma cells where Fas and TRAIL receptors or just TRAIL receptors were inhibited using mutants of the adaptor protein FADD or by altering the expression of the homeobox transcription factor Six1. Inhibition of TRAIL receptors did not affect in vitro tumor cell killing by various anti-cancer agents indicating that chemosensitivity is not significantly affected by the tumor cell-intrinsic activation of death receptor signaling. However, selective inhibition of TRAIL receptor signaling caused reduced tumor regression and clearance in vivo when tested in a NOD/SCID mouse model.


CONCLUSIONS
These data show that TRAIL receptor signaling in tumor cells can determine chemosensitivity in vivo but not in vitro and thus imply that TRAIL resistance makes tumors less susceptible to conventional cytotoxic anti-cancer drugs as well as drugs that directly target the TRAIL receptors.
Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
Christina
C
Menke
Tatiana
T
Goncharov
Lubna
L
Qamar
Christopher
C
Korch
Heide L
HL
Ford
Kian
K
Behbakht
Andrew
A
Thorburn
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand
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