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Phospho-Sulindac Inhibits Pancreatic Cancer Growth: The Role of NFATc1

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dc.contributor.advisor Rigas, Basil en_US
dc.contributor.author Murray, Onika T. en_US
dc.contributor.other Department of Molecular and Cellular Pharmacology en_US
dc.date.accessioned 2013-05-22T17:35:18Z
dc.date.accessioned 2015-04-24T14:47:10Z
dc.date.available 2013-05-22T17:35:18Z
dc.date.available 2015-04-24T14:47:10Z
dc.date.issued 2012-08-01 en_US
dc.identifier Murray_grad.sunysb_0771E_11008 en_US
dc.identifier.uri http://hdl.handle.net/1951/59799 en_US
dc.identifier.uri http://hdl.handle.net/11401/71355 en_US
dc.description 141 pg. en_US
dc.description.abstract While significant progress has been made in the battle against pancreatic cancer, it ranks 4th in cancer-related deaths in the U.S. Lending to the lethality of the disease is its ability to grow virtually undetected. Once pancreatic cancer is diagnosed, chances are that it has advanced beyond the point of surgical resection, as well as having become quite resistant to chemotherapy. While some chemotherapeutic agents have been able to improve patients' short-term quality of life, the impact on long-term survival has been minimal. The Nuclear Factor of Activated T-cells (NFAT) family is a calcineurin-responsive group of transcription factors initially identified as regulators of T-lymphocyte activation, though they are ubiquitously expressed in cells throughout the body. In particular, NFATc1 has been shown to be overexpressed in pancreatic cancer, thus adding to the aggressive nature of the disease. In preliminary studies with our novel compound, phospho-sulindac (P-S), NFATc1 gene expression and protein levels were elevated in response to treatment. This finding prompted us to study the effects of P-S both in the absence and the abundance of NFATc1. My research focuses specifically on the effects that altered expression of NFATc1 (by genetically and pharmacologically silencing or by overexpressing it) has on pancreatic cancer growth in vitro and in vivo. We found that when the expression of NFATc1 was abrogated either by RNAi or pharmacological inhibition, pancreatic cancer cells were more responsive to treatment with P-S. In the same way, overexpressing the NFATc1 gene made the pancreatic cancer cells less responsive to treatment with P-S. NFATc1 localization is indicative of its activity, with nuclear localization being the active form. Treatment of pancreatic cancer cells with P-S facilitated the cytosolic localization of NFATc1. NFATc1 knock-down and overexpression animal models were generated and the effect of P-S on tumor growth was analyzed. We observed the greatest reduction in tumor growth in our NFATc1 knock-down model. We conclude that P-S is a potentially important agent for the treatment of pancreatic cancer and that NFATc1 localization and activation in response to our compound may play a role in its pharmacological action. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Pharmacology--Molecular biology en_US
dc.subject.other Cancer, NFATc1, NSAID, Pancreatic Cancer, Phosphosulindac en_US
dc.title Phospho-Sulindac Inhibits Pancreatic Cancer Growth: The Role of NFATc1 en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Miller, Todd en_US
dc.contributor.committeemember Keresztes, Roger en_US
dc.contributor.committeemember Crawford, Howard. en_US

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