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CD73 Participates in Cellular Multiresistance Program and Protects against TRAIL-Induced Apoptosis¹

Andrey Mikhailov^*, Alice Sokolovskaya, Gennady G. Yegutkin, Hanne Amdahl^*, Anne West^*, Hideo Yagita, Riitta Lahesmaa^*, Linda F. Thompson^¶, Sirpa Jalkanen, Dmitry Blokhin and John E. Eriksson^2,*

^* Turku Centre for Biotechnology, University of Turku/Åbo Akademi University, Turku, Finland; Cancer Research Center, Moscow, Russia; Medicity, University of Turku, Turku, Finland; Department of Immunology, School of Medicine, Juntendo University, Tokyo, Japan; ^¶ Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104; and ^|| Department of Biology, Åbo Akademi University, Turku, Finland

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Academy of Finland and the National Technology Agency, and National Institutes of Health Grant AI18220 (to L.F.T.). L.F.T. holds the Putnam City Schools Distinguished Chair in Cancer Research.

² Address correspondence and reprint requests to Dr. John E. Eriksson, Department of Biology, Åbo Akademi University, Tykistokatu 6B, FIN-20520 Turku, Finland. E-mail address: john.eriksson{at}abo.fi

³ Abbreviations used in this paper: TLC, thin-layer chromatography; PI-PLC, phosphatidylinositol-specific phospholipase C; FADD, Fas-associated death domain; HSP, heat shock protein; HSC, heat shock cognate; AMPCP, ,β-methylene adenosine 5'-diphosphate; DISC, death receptor signaling complex; siRNA, short interfering RNA; BID, BH3-interacting domain death agonist.