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

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Murray, Onika T.
The Graduate School, Stony Brook University: Stony Brook, NY.
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.
141 pg.