The molecular mechanisms underlying the multiresistant phenotype of
leukemic and other cancer cells are incompletely understood. We used
expression arrays to reveal differences in the gene expression profiles
of an apoptosis-resistant T cell leukemia clone (A4) and normally
apoptosis-sensitive parental Jurkat cells. CD73 (ecto-5'-nucleotidase)
was the most up-regulated gene in the resistant A4 cell clone. A4 cells
displayed CD73 surface expression and significant ecto-5'-nucleotidase
activity. The role of CD73 was confirmed by transfection of wild-type
CD73 into native Jurkat cells, which led to specific resistance against
TRAIL-induced apoptosis, but not other types of apoptosis. The
protective role of CD73 was further confirmed by small interfering
RNA-mediated down-regulation of CD73, restoring TRAIL sensitivity.
CD73-mediated resistance was independent of enzymatic activity of CD73,
but was reliant on the anchoring of the protein to the membrane via GPI.
We suggest that the inhibition of TRAIL signaling works through
interaction of CD73 with death receptor 5, as CD73 and death receptor 5
could be coimmunoprecipitated and were shown to be colocalized in the
plasma membrane by confocal microscopy. We propose that CD73 is a
component of multiresistance machinery, the transcription of which is
activated under selective pressure of the immune system.