The Tumor Suppressive Effects of T Cell Death-Associated Gene 8 in Blood Cancers

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)
Calvin Richard Justus (Creator)
East Carolina University (ECU )
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Abstract: In the early twentieth century Otto Warburg recognized a metabolic phenomenon that transpired in cancer cells , currently known as the Warburg Effect. Warburg discovered cancer cells favor glycolysis rather than oxidative phosphorylation for energy production , even in the presence of oxygen. As a result of increased glycolytic flux in cancer cells the tumor microenvironment is acidic. Extracellular acidosis has pleiotropic effects on tumor growth and cancer progression. Therefore , it is important to understand how cancer cells sense extracellular acidosis and respond to it. Cancer cells can sense extracellular acidosis through the proton-sensing G-protein-coupled receptor family , which includes GPR65 (TDAG8) , GPR4 , GPR68 (OGR1) , and GPR132 (G2A). In this study , a bioinformatics analysis revealed T cell death-associated gene 8 (TDAG8) expression is significantly reduced in human hematologic malignancies when compared with normal immune cells and leukocyte-rich tissue. This observation prompts the hypothesis that TDAG8 gene expression is unfavorable for cancer progression of hematologic malignancies. To test the hypothesis , TDAG8 gene expression was restored in U937 acute myeloid leukemia cells. Upon investigation , severe extracellular acidosis inhibited U937 cell proliferation while mild acidosis stimulated it. However , restoration of TDAG8 gene expression reduced U937 cell proliferation. Restoring TDAG8 gene expression in various blood cancer cell lines also reduced tumor growth in severe combined immuno-deficient mice , which correlated with a significant reduction in c-myc oncogene expression. Investigations demonstrated TDAG8 activates G[alpha]13/RhoA signaling to reduce c-myc oncogene expression in U937 cells. G[alpha]13/RhoA signaling is crucial for cell attachment , migration , and metastasis. Consequently , metastasis was investigated with U937 cells. Restoring TDAG8 gene expression reduced U937 cell attachment to matrigel , migration toward a chemoattractant , and metastasis in severe combined immuno-deficient mice. Overall , this dissertation provides evidence that TDAG8 delivers a growth disadvantage to cancer cells of hematologic origin and acts as a contextual tumor suppressor.

Additional Information

Language: English
Date: 2017
G-protein-coupled receptor, tumor microenvironment, cancer

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