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Loss of CD73-mediated actin polymerization promotes endometrial tumor progression
Jessica L. Bowser, … , Kenneth Dunner Jr., Russell R. Broaddus
Jessica L. Bowser, … , Kenneth Dunner Jr., Russell R. Broaddus
Published December 7, 2015
Citation Information: J Clin Invest. 2016;126(1):220-238. https://doi.org/10.1172/JCI79380.
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Research Article Oncology

Loss of CD73-mediated actin polymerization promotes endometrial tumor progression

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Abstract

Ecto-5′-nucleotidase (CD73) is central to the generation of extracellular adenosine. Previous studies have highlighted a detrimental role for extracellular adenosine in cancer, as it dampens T cell–mediated immune responses. Here, we determined that, in contrast to other cancers, CD73 is markedly downregulated in poorly differentiated and advanced-stage endometrial carcinoma compared with levels in normal endometrium and low-grade tumors. In murine models, CD73 deficiency led to a loss of endometrial epithelial barrier function, and pharmacological CD73 inhibition increased in vitro migration and invasion of endometrial carcinoma cells. Given that CD73-generated adenosine is central to regulating tissue protection and physiology in normal tissues, we hypothesized that CD73-generated adenosine in endometrial carcinoma induces an innate reflex to protect epithelial integrity. CD73 associated with cell-cell contacts, filopodia, and membrane zippers, indicative of involvement in cell-cell adhesion and actin polymerization–dependent processes. We determined that CD73-generated adenosine induces cortical actin polymerization via adenosine A1 receptor (A1R) induction of a Rho GTPase CDC42–dependent conformational change of the actin-related proteins 2 and 3 (ARP2/3) actin polymerization complex member N-WASP. Cortical F-actin elevation increased membrane E-cadherin, β-catenin, and Na+K+ ATPase. Together, these findings reveal that CD73-generated adenosine promotes epithelial integrity and suggest why loss of CD73 in endometrial cancer allows for tumor progression. Moreover, our data indicate that the role of CD73 in cancer is more complex than previously described.

Authors

Jessica L. Bowser, Michael R. Blackburn, Gregory L. Shipley, Jose G. Molina, Kenneth Dunner Jr., Russell R. Broaddus

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Figure 10

Adenosine A1R induces actin polymerization.

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Adenosine A1R induces actin polymerization.
(A) Representative immunoblo...
(A) Representative immunoblot of total actin isolated from confluent HEC-1-A cells treated with DMSO (0.001%) or 100 nM, 1 μM, or 10 μM of the A1R agonist CPA in hypoxia (1% O2, 5%) for 36 hours. Graph shows densitometric data for 4 independent experiments. (B) Alexa Fluor–conjugated phalloidin in DMSO- and CPA-treated HEC-1-A cells. Scale bars: 20 μm. (C) F-actin intensity was assessed in 10 or more images (original magnification, ×20). (D) Schematic of Rho GTPase CDC42 and the ARP2/3 actin polymerization complex member N-WASP. CDC42 binds to N-WASP, releasing its autoinhibited state. (E) Co-IP. HEC-1-A cells (90% confluent) were transfected with 2 μg Myc-tagged CDC42 or 2 μg Myc-tagged N-WASP 24 hours before hypoxia and then treated with DMSO (0.001%) or 10 μM CPA in hypoxia (1% O2, 5% CO2) for 36 hours. Co-IP immunoblots are representative of 3 (Myc-CDC42) and 2 (Myc-N-WASP) independent experiments (for experimental replicates, see Supplemental Figure 15). NT, nontransfected. Data represent the mean ± SEM. **P < 0.001; 1-way ANOVA with Tukey’s post test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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