Downregulation of endogenous TRAIL and its effect on the human cancer cell line KELLY

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has
been shown to exert an unexpected pro-survival, pro-proliferative
and pro-invasive effect on a subset of human cancer cell lines.
Recent clinical studies report that increased expression of
endogenous TRAIL is associated with decreased disease-specific
survival in renal cell carcinoma and cholangiocarcinoma which are
resistant to TRAIL induced apoptosis. The present work investigated
the role of endogenous TRAIL as an intrinsic growth factor in
apoptosis-resistant human cancer cells. Several cell lines derived
from solid human tumors were studied, among them the neuroblastoma
cell line KELLY, a cancer cell line resistant to TRAIL-induced
apoptosis. First, to investigate whether TRAIL-knockdown could
inhibit cell growth, the use of small interfering RNAs (siRNA) for
endogenous TRAIL was established and a successful knockdown was
verified on both mRNA and protein level. Second, the functional
impact of the knockdown of endogenous TRAIL was investigated by
measuring cell growth and cell death after transfection:
Interestingly, the human neuroblastoma cell line KELLY unexpectedly
showed markedly reduced cell growth upon knockdown of endogenous
TRAIL. Furthermore, knockdown of TRAIL induced cell death in KELLY
cells, which was dependent on caspase-signaling and rescued by the
addition of soluble TRAIL. Thus, endogenous TRAIL functions as an
intrinsic survival and growth factor in the neuroblastoma cell line
KELLY. The present work provided first evidence that the expression
of endogenous TRAIL can be specifically downregulated through siRNA
knockdown to inhibit survival and growth of cancer cells in-vitro,
which are resistant to TRAIL induced apoptosis. The present data
strongly supports the potential of endogenous TRAIL to function as
a novel therapeutic target in cancer therapy. In the light of the
emerging clinical use of siRNAs for cancer therapy, targeting TRAIL
by RNA interference may provide a valuable treatment approach for
patients with cancers resistant to TRAIL induced apoptosis and high
expression levels of endogenous TRAIL.