Natural Agent in Prevention of Prostate Cancer

 描述（由申请方提供）：拟定研究将确定薯蓣皂苷（一种天然植物黄烷醇）在调节Rictor中的化学预防潜力; Rictor是mTORC 2（雷帕霉素不敏感）蛋白复合物功能中的核心成分和关键蛋白，可预防前列腺癌进展。据报道，Rictor在结肠癌、乳腺癌和卵巢癌中的作用。循环生长因子使前列腺癌细胞中Thr-1135处的Rictor蛋白磷酸化，此外，Rictor的存在增加导致一系列事件，包括PKCa和Akt分子的磷酸化。这两种分子在细胞存活、细胞粘附、细胞转化和细胞周期调节中起重要作用。已经证明，已知的mTOR激酶通路抑制剂雷帕霉素对Rictor（mTORC 2主要成分）没有抑制作用。迫切需要的是确定一种有效的药物，可以调节Rictor及其相关事件PKCa和Akt，以防止前列腺癌的进展。薯蓣皂苷具有抗炎、抗氧化和抗癌作用。该研究将探讨薯蓣皂苷在前列腺癌中靶向Rictor、其磷酸化及其相关信号传导事件的预防作用。体外和体内研究将确定薯蓣皂苷是否具有抑制Rictor，其磷酸化， 并且另外维持Rictor的存在以将PKCa和Akt的激酶活性调节在适当水平，从而导致前列腺癌细胞增殖和肿瘤进展减少。我们的长期目标是开发一种安全有效的前列腺癌化学预防剂，并了解Rictor在前列腺癌进展中的作用。公共卫生意义：迫切需要一种有效的和临床相关的策略来抑制前列腺癌，副作用最小。因此，使用来自柑橘类水果和草药制剂的天然试剂，将测试薯蓣皂苷的潜力 对抗前列腺癌由于前列腺癌是美国男性的第二大杀手，因此迫切需要减少这种致命疾病的死亡人数。

 DESCRIPTION (provided by applicant): The proposed study will determine the chemo-preventive potential of diosmetin, a natural plant flavanol, in regulating Rictor; the core constituent and critical protein in the function of mTORC2 (rapamycin- insensitive) protein complex to prevent prostate cancer progression. The role of Rictor has been reported in colon, breast and ovarian cancers. Circulating growth factors phosphorylates Rictor protein at Thr-1135 in prostate cancer cells, moreover, increased presence of rictor results in series of events including phosphorylation of PKCa and Akt molecules. Both these molecules play significant role in cell survival, cell adhesion, cell transformation and cell cycle regulation. It has been demonstrated that rapamycin, the known inhibitor of mTOR kinase pathway has no inhibitory effect on Rictor (mTORC2 main component). The urgent need is to identify an effective agent that can regulate Rictor and its associated events PKCa and Akt to prevent prostate cancer progression. Diosmetin has anti- inflammatory, anti-oxidants and anticancer effects. The proposed study will explore the preventive role of diosmetin in targeting Rictor, its phosphorylation and also its associated signaling events in prostate cancer. The in vitro and in vivo studies will determine whether diosmetin has potential to inhibit Rictor, its phosphorylation, and additionally maintain rictor's presence to regulate kinase activities of PKCa and Akt at appropriate level, thereby resulting in reduced prostate cancer cell proliferation and tumor progression. Our long term goal is to develop diosmetin as safe and an effective chemopreventive agent for prostate cancer and to understand the role of Rictor in prostate cancer progression. Public Health Significance: There is an immediate need for an effective and clinically relevant strategy to inhibit prostate cancer, with minimal side-effects. Hereby using a natural agent from citrus fruits and herbal preparations, the potential of diosmetin will be tested against prostate cancer. Since prostate cancer is the second largest killer in the United States males, reducing deaths from this deadly form of disease is urgently needed.