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Genetic deletion and inhibition of selenoprotein K reduces melanoma growth and metastasis by altering intracellular calcium
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|Marciel hawii 0085A 10244.pdf||3.75 MB||Adobe PDF||View/Open|
|video 1.mp4||9.49 MB||MPEG-4||View/Open|
|dc.contributor.advisor||Hoffmann, Peter R.|
|dc.contributor.author||Marciel, Michael P.|
|dc.title||Genetic deletion and inhibition of selenoprotein K reduces melanoma growth and metastasis by altering intracellular calcium|
|dc.contributor.department||Cell and Molecular Biology|
|dcterms.abstract||Melanoma is the deadliest form of skin cancer, resulting in over 9,000 deaths annually in the United States alone. Along with limiting ultraviolet exposure, it is vital that new therapies are generated that target melanoma progression. A recent interest in targeting store operated calcium entry (SOCE) as a treatment for different cancers types has recently emerged. SOCE is the main mechanism by which non-excitable cells import calcium (Ca2+) from the extracellular space and this process is critical for normal growth, proliferation, and migration in a variety of cell types. Several studies have demonstrated that knockdown or complete genetic deletion of SELENOK reduced SOCE in immune cells and retarded their ability to differentiate, proliferate, and migrate. However, the effect of inhibiting SELENOK in cancer has not yet been investigated. We hypothesized that deletion of SELENOK in melanoma cells may decrease their ability to proliferate and metastasize by a reducing SOCE. This hypothesis was tested using three approaches (i) SELENOK null mice were crossed with a murine model of melanoma, and melanoma progression in the absence of SELENOK was observed, (ii) SELENOK null melanoma cells were generated using a CRISPR-Cas9 approach in a human melanoma cell line, and tested for their ability to proliferate and migrate in vitro, and, (iii) an inhibitor based on the structure of SELENOK was generated and tested for its ability to inhibit the SELENOK mediated palmitoylation in a cell free environment. The data presented herein show that SELENOK deletion inhibited calcium flux and calcium dependent signaling in vitro which reduced that capacity of melanoma cells to migrate and proliferate. Furthermore, SELENOK deletion decreased primary growth and metastasis of tumor cells in a spontaneous mouse model of melanoma. Last, the inhibitor based on SELENOK was shown to be able to disrupt SELENOK mediated palmitoylation and thus may serve as a basis for future inhibitors. This dissertation will attempt to outline the data representing the first investigation into the role of SELENOK in metastatic melanoma.|
|dcterms.description||Ph.D. Thesis. Ph.D. Thesis. University of Hawaiʻi at Mānoa 2019|
|dcterms.publisher||University of Hawai'i at Manoa|
|dcterms.rights||All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.|
|Appears in Collections:||
Ph.D. - Cell and Molecular Biology|
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