The Inhibition of HSP70 Induces Apoptosis in Pancreatic Cancer Cells

抑制 HSP70 诱导胰腺癌细胞凋亡

基本信息

批准号：
7670265
负责人：
ASHOK K SALUJA
金额：
$ 28.41万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-24 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7670265
关键词：
Adjuvant Apoptosis Apoptosis Inhibitor Apoptotic Attenuated Biological Calcium Calcium Signaling Cancer Etiology Cancer cell line Cell Death Cell Membrane Permeability Cell Survival Cells Cessation of life Development Diagnosis Diagnostic Neoplasm Staging Disease Down-Regulation Growth Heat shock proteins Heat-Shock Proteins 70 Human In Vitro Inhibition of Apoptosis Laboratories Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Membrane Mitochondria Modeling Molecular Morphology Mus Neoplasm Metastasis Outcome Pancreas Pancreatic Intraepithelial Neoplasia Pancreatic duct Patients Permeability Pharmaceutical Preparations Play Predisposition Property Quercetin Reporting Resistance Role Severities Small Interfering RNA Specimen Staging TNM Testing Tumor stage United States Up-Regulation antitumor drug cancer cell cell type chemotherapeutic agent chemotherapy cytochrome c design effective therapy in vivo inhibitor/antagonist innovation mouse model neoplastic cell novel outcome forecast overexpression palliative chemotherapy pancreatic neoplasm prevent response stress protein tool triptolide tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：这项研究对胰腺癌细胞的总体目的是1）研究HSP70如何防止细胞凋亡并促进这些细胞的存活和2）阐明抑制HSP70的机制会导致细胞凋亡。胰腺癌是一种毁灭性的疾病，预后不良，是美国与癌症相关死亡的第四个主要原因。这是因为胰腺癌细胞对凋亡具有抗性，导致对辅助和姑息化疗的反应不佳，因此患者的生存率差。我们小组的最新研究表明，HSP70在胰腺癌细胞中被上调，并且HSP70抑制导致细胞凋亡导致细胞死亡。拟议的研究将检验以下假设：HSP70的这种过表达对于恶性胰腺细胞的存活至关重要，并且其表达的降低使它们更容易凋亡，抑制其生长，增加其对化学治疗剂的易感性。我们提出以下四个特定旨在检验该假设的有效性的特定旨在。 1）检查胰腺癌细胞中的HSP70水平，并将这些水平与这些细胞的转移潜力和化学耐药性相关联； 2）检查HSP70的抑制是否导致胰腺癌细胞凋亡增加； 3）研究通过抑制Hsp70表达引起的细胞内钙变化的机制，导致线粒体细胞色素c的释放导致细胞凋亡； 4）为了阐明通过抑制HSP70诱导溶酶体膜通透性导致胰腺癌细胞凋亡的机制。这些研究的成功完成最终将有助于计划策略，以操纵HSP70的水平，以便将其抑制作用用作降低胰腺癌严重程度的工具。胰腺癌是一种预后不良的毁灭性疾病，是美国与癌症相关死亡的第四个主要原因。这种恶性肿瘤的严重性可以通过以下事实来理解：仅在2005年，就诊断出32,180例新病例，几乎相同的数量屈服于该疾病。因此，迫切需要努力获取有关胰腺癌病理生物学的信息，并迫切需要与肿瘤细胞的侵袭/转移相关的分子机制来开发创新有效的治疗。我们认为，对当前化疗药物的耐药性主要是由于肿瘤中HSP70水平升高。因此，这项研究的总体目的是1）研究HSP70在防止胰腺癌细胞凋亡中的作用，以及2）阐明HSP70抑制导致胰腺癌细胞凋亡的机制。了解胰腺癌逃避细胞凋亡的机制将有助于识别并最终设计这种致命疾病的新型疗法。