Advanced colorectal carcinoma is currently incurable, and currently has a five-year survival rate of only 13.8%. New therapies are urgently needed for the treatment of the second most deadly cancer in the western world. Eph (erythropoietin-producing human hepatocellular) receptors comprise the largest family of receptor tyrosine kinases. Eph receptors are activated by membrane bound Ephrin ligands. In the intestine, disruption of EphB/EphrinB signaling leads to malformed intestinal architecture indicating these molecules controls cell positioning during normal physiology. The role of these molecules in colorectal cancer is currently unclear.
In this dissertation, I report that phosphotyrosine-dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. I find that genetic or biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2, reproducibly induce colorectal carcinoma cell death by autophagy. Spautin, an inhibitor of early steps in the autophagic pathway, significantly reduces autophagic cell death that follows inhibition of phosphotyrosine-dependent Eph signaling in colorectal cancer cells. A small-molecule the Eph kinase inhibitor, NVP-BHG712 or its regioisomer NVP-Iso, reduce human colorectal cancer cell growth in vitro and tumor growth in mice. Colorectal cancers express the EphrinB ligand and its Eph receptors at higher levels than other cancer types, supporting Eph signaling inhibition as a potential new strategy for the broad treatment of colorectal carcinoma.
|Advisor:||Tosato, Giovanna, Lee, Norman|
|Commitee:||Daar, Ira, Nazarian, Javad, Lipkowitz, Stanley, Chung, Inhee|
|School:||The George Washington University|
|Department:||Biochemistry & Systems Biology|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Biochemistry, Oncology|
|Keywords:||Autophagy, Colorectal cancer, Ephrin receptor|
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