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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 8

The adenosine A1R antagonist DPCPX decreases cortical F-actin.

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The adenosine A1R antagonist DPCPX decreases cortical F-actin.
(A) Adeno...
(A) Adenosine receptor mRNA expression by real-time qPCR. (B) Representative immunoblot of total actin isolated from confluent HEC-1-A cells treated with DMSO (0.001%), 10 μM NECA, 10 μM NECA plus the A1R antagonist DPCPX (10 μM) or plus the A2BR antagonist MRS1754 (10 μM) in hypoxia (1% O2, 5% CO2) for 36 hours. Graph shows densitometric data from 5 independent experiments. (C) HEC-1-A cells labeled with Alexa Fluor–conjugated phalloidin. (D) F-actin intensity was assessed in 10 or more images (original magnification, ×20). Data represent the mean ± SEM. **P < 0.005 compared with DMSO; *P < 0.05 compared with NECA; and #P < 0.001 compared with NECA plus MRS1754; 1-way ANOVA with Tukey’s post test. Scale bars: 20 μm.

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