The overall aims of this study on pancreatic cancer cells are 1) to investigate how HSP70 prevents apoptosis and promotes survival of these cells and 2) to elucidate the mechanisms by which inhibition of HSP70 results in apoptosis. Pancreatic cancer is a devastating disease with a poor prognosis and is the fourth leading cause of cancer-related death in the US. This is because pancreatic cancer cells are resistant to apoptosis, resulting in poor response to adjuvant and palliative chemotherapy and thus poor patient survival. Recent studies by our group indicate that HSP70 is upregulated in pancreatic cancer cells and that inhibition of HSP70 leads to cell death by apoptosis. The proposed studies will test the hypothesis that this over-expression of HSP70 is essential for the survival of malignant pancreatic cells, and that a reduction of its expression renders them more prone to apoptosis, inhibits their growth and increases their susceptibility to chemotherapeutic agents. We propose the following four specific aims to test the validity of this hypothesis. 1) To examine HSP70 levels in pancreatic cancer cells and correlate these levels with the metastatic potential and chemoresistance of these cells;2) To examine whether inhibition of HSP70 leads to increased apoptosis of pancreatic cancer cells;3) To study the mechanism by which changes in intracellular calcium induced by the inhibition of HSP70 expression cause the release of mitochondrial cytochrome c resulting in apoptosis;and 4) To elucidate the mechanisms by which lysosomal membrane permeabilization induced by the inhibition of HSP70 results in apoptosis of pancreatic cancer cells. The successful completion of these studies will eventually help plan strategies to pharmacologically manipulate the levels of HSP70, so that its inhibition can be used as a tool to decrease the severity of pancreatic cancer.Narrative Pancreatic cancer, a devastating disease with a poor prognosis, is the fourth leading cause of cancer-related deaths in the United States. The severity of this malignancy can be appreciated by the fact that in 2005 alone, 32,180 new cases were diagnosed, with almost the same number succumbing to the disease. Hence, efforts to gain information on the pathobiology of pancreatic cancer and to elucidate the molecular mechanisms related to the invasion/metastasis of the tumor cells are urgently needed to develop innovative and effective treatments. We believe that resistance to current chemotherapy drugs is primarily due to increased levels of HSP70 in the tumors. Therefore, the overall aims of this study are 1) to investigate the role of HSP70 in preventing pancreatic cancer cells from undergoing apoptosis and 2) to elucidate the mechanisms by which the inhibition of HSP70 results in apoptosis of pancreatic cancers. Understanding the mechanisms by which pancreatic cancer evades apoptosis will help to identify and eventually design novel therapies with which to treat this deadly disease.
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