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

Abstract

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.

Extracellular adenosine triphosphate and adenosine in cancer

“…In addition, CD73 expression was increased in breast tumor cells resistant to doxorubicin (Ujhazy et al, 1996). CD73 also increased the resistance of Jurkat leukemic cells to tumor necrosis factor-related apoptosis-inducing ligandmediated apoptosis (Mikhailov et al, 2008).…”

“…CD73 on cancer cells. CD73 has been found to be overexpressed in several types of cancer, including bladder cancer (Stella et al, 2010), leukemia (Mikhailov et al, 2008), glioma (Bavaresco et al, 2008), glioblastoma (Ludwig et al, 1999), melanoma (Sadej et al, 2006), ovarian cancer (Jin et al, 2010), thyroid cancer (Kondo et al, 2006), esophageal cancer (Fukuda et al, 2004), gastric cancer (Durak et al, 1994), colon cancer (Eroglu et al, 2000), prostate cancer and breast cancer . Notably, CD73 expression has been associated with a pro-metastatic phenotype in melanoma and breast cancer (Lee et al, 2003;LethLarsen et al, 2009).…”

Potential prognostic biomarker CD73 regulates epidermal growth factor receptor expression in human breast cancer

“…Although many of the CD73 effects are consequences of its adenosine production, also more direct interactions have been reported. The protection from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is thought to be mediated by direct binding of CD73 to the death receptor 5, instead of enzymatic activity of CD73 (21). Recently, Supernat et al studied CD73 expression in 136 consecutive stage I-III breast cancer patients.…”

Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia

“…Highly expressed in this group of patients with the worst outcome were genes (BMPR1B, CTGF [CCN2], TTYH2, IGJ, PON2, CD73, CDC42EP3, TSPAN7, and SEMA6A) involved in adaptive cell signaling responses to transforming growth factor ␤, stem cell function, B-cell development and differentiation, and the regulation of tumor growth. [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] These highest risk cases lacked expression of the genes (NR4A3, BTG3, RGS1, and RGS2) whose relatively high expression characterized the ALL cases with the best outcome. Not surprisingly, given that all cases with an activated kinase signature were assigned to the highest risk group with the combined classifier, 6 of the genes associated with our kinase signature (BMPR1B, ECM1, IGJ, PON2, SEMA6A, and TSPAN7) were contained within our gene expression classifier for RFS.…”