THE ROLE OF CALCIUM SIGNALING ON PTEN REGULATION

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DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is lethal disease that comprises 15% of all gastrointestinal cancers. The incidence of pancreatic cancer has increased to >37,680 new cases and 34,290 deaths due to this disease in 2008 in the U.S. alone. Pancreatic adenocarcinoma, making up over 90% of pancreatic cancer, is characterized by poor survival and resistance to radio-chemotherapy and thus novel therapeutic strategies are urgently required. Cancer formation and growth are based on increased cell proliferation and/or decreased apoptosis, and cancer invasion and metastasis are associated with increased cell migration. Our previous studies have found that PTEN is an important tumor suppressor that was downregulated by TGF2 via induction of cytosolic free Ca2+ concentration ([Ca2+]cyt). [Ca2+]cyt is essential to cell proliferation, apoptosis, and cell migration . The levels of [Ca2+]cyt are often elevated in cancer cells, making [Ca2+]cyt homeostasis an important focus in current cancer research. [Ca2+]cyt homeostasis is controlled by membrane Ca2+ channels and transporters, of which store-operated Ca2+ channels (SOC) are important candidates. SOC is a major regulator of [Ca2+]cyt in non-excitable epithelial cells. Although the molecular identity of SOC is still uncertain, work in this area has focused on transient receptor potential canonical (TRPC) channels on the basis of observations that expression of TRPC leads to the formation of Ca2+- permeable channels activated by receptor activation and store depletion3, 4. It is now accepted that TRPC1 is recognized to function as SOC in intestinal epithelial cells5, 6. Although TRPC has been shown recently to play an important role in tumorigenesis in gastric and ovarian cancers, its role in pancreatic cancer has not been studied to date. Our preliminary data demonstrated that TGF2-induced [Ca2+]cyt led to PTEN downregulation and that TRPC1 expressed in pancreatic cancer cells facilitated Ca2+ entry to promote pancreatic tumorigenesis. Therefore, the objective of the current proposal is to test the hypothesis that Ca2+ enrty through TRPC1-encoded SOC promotes TGF2-mediated PTEN downregulation and pancreatic cancer cell migration. PUBLIC HEALTH RELEVANCE: The clinical significance is from the fact that PTEN appears to play an important role in pancreatic tumorigenesis and metastasis. Pancreatic cancer is a lethal disease and cancer cells are resistant to conventional once metastasis. The findings from the proposal will shed light on novel treatment strategies to patients with pancreatic cancer