Phytochemicals, ER-Stress and Prostate Cancer

植物化学物质、内质网应激和前列腺癌

• 批准号: 6763033
• 负责人: KAREN J AUBORN
• 金额: $ 28.77万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-19 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6763033
• 关键词: CHO cells; apoptosis; cancer prevention; chemoprevention; endoplasmic reticulum; genistein; indoles; laboratory mouse; messenger RNA; microarray technology; molecular chaperones; neoplastic cell; neoplastic growth; nutrition aspect of cancer; nutrition related tag; prostate neoplasms; stress proteins; tunicamycin; xenotransplantation

DESCRIPTION (provided by applicant): Our overall goal is to determine mechanisms whereby genistein, the major isoflavone in soybeans, prevents growth and induces apoptosis of prostate cancer cells. Both prospective and retrospective epidemiologic studies indicate that soy products decrease the risk of prostate cancer. Laboratory studies support the epidemiology. This proposal asks specifically about the role of genistein and other nutrients as a response to metabolic stress, and whether genistein influences the stress response to specifically target cancer cells for death. In vivo, cancer cells are likely to be chronically metabolically stressed, because their unregulated growth taxes the capacity of existing or newly recruited vaculature. The metabolic stress proteins known as the glucose regulated proteins (GRPs) protect tumor cells from apoptosis, whereas the metabolic stress proteins known as growth-arrest-DNA-damage proteins (GADDs) cause growth arrest and apoptosis. The hypothesis to be tested is that genistein, by selectively inhibiting GRPs, but not GADDs, induces growth arrest and apoptosis of prostate cancer cells. This study will: 1) characterize the effects of genistein on mRNA and protein levels for the stress-related GRP genes (grp78 and grp94) and the GADD genes (GADD153 and GADD45) in cells before and after exposure to stress inducing agents, 2) compare the effects of genistein on growth and apoptosis of stressed and non-stressed cells, 3) compare the effects of genistein on growth arrest and apoptosis in cells that over-express grp78, a protective chaperonin, after treatment with stress-inducing agents, and 4) determine whether genistein acts synergistically with other dietary compounds, e.g. diindolylmethane-derived from cruciferous vegetables which induces expression of GADDs and determine whether the mechanism involves pathways of the ER-stress response. If our hypothesis is correct, the exciting implication is that this is a mechanism whereby certain bioactive compounds in food can specifically target cancer cells for death. Moreover, combinations of nutrients may work together and at lower concentrations to target cancer cells.

描述（由申请人提供）： 我们的总体目标是确定机制，在这种机制中，染料木黄酮是大豆中主要的异黄酮，可防止生长并诱导前列腺癌细胞的凋亡。 前瞻性和回顾性流行病学研究都表明，大豆产品降低了前列腺癌的风险。 实验室研究支持流行病学。 该提议特别询问染料木黄酮和其他营养作为对代谢应激的反应的作用，以及染料木黄酮是否影响对特异性靶向癌细胞死亡的应激反应。 在体内，癌细胞可能会在代谢上长期压力，因为它们的不受管制的生长税是现有或新招募的真空的能力。 称为葡萄糖调节蛋白（GRP）的代谢应激蛋白可保护肿瘤细胞免受凋亡的影响，而代谢应激蛋白被称为生长降落 - DNA破坏蛋白（GADDS）会导致生长停滞和凋亡。 要检验的假设是，通过选择性抑制GRP而非GADDS，染料木黄酮会诱导前列腺癌细胞的生长停滞和凋亡。 这项研究将：1）在与压力相关的GRP基因（GRP78和GRP94）（GRP78和GRP94）以及GADD基因（GADD153和GADD45）中对压力相关的GRP基因（GADD153和GADD45）在与压力诱导诱导药物发生之前和之后的细胞中的影响表征染料蛋白酶对MRNA和蛋白水平的影响。在用压力诱导剂治疗后过表达GRP78（一种保护性伴侣蛋白）的细胞中的细胞凋亡，以及4）确定染料木黄酮是否与其他饮食化合物协同作用，例如从十字花科蔬菜中衍生的苯甲烷源性蔬菜，这些蔬菜诱导了GADDS的表达，并确定该机制是否涉及ER压力反应的途径。如果我们的假设是正确的，那么令人兴奋的含义是，这是一种机制，食物中某些生物活性化合物可以特异性地靶向癌细胞死亡。 此外，养分的组合可以共同起作用，并且在较低浓度的靶向癌细胞中起作用。