Prostate Cancer--Mechanisms of Bax induced Cell Death

前列腺癌细胞对雄激素不依赖性的发展是传统治疗前列腺癌的主要障碍。主要的分子缺陷是癌细胞无法启动程序性细胞死亡（凋亡）以响应各种促消化刺激。最近我们发现bad是一种促凋亡分子，是BCL-2的对偶物，它的过度表达包括前列腺癌细胞的凋亡。事实上，雄激素非依赖性LNCaP细胞比雄激素依赖性LNCaP细胞对bad诱导的细胞死亡更敏感。此外，Bad的亚细胞定位在雄激素依赖性和非依赖性LNCaP细胞中似乎是不同的。我们假设Bad可能在雄激素非依赖型前列腺癌的细胞存活和死亡之间的平衡中发挥关键作用。我们拟在体外和体内研究bad诱导前列腺癌细胞凋亡的分子机制及其与雄激素非依赖性的关系。这项工作是新颖的，因为它将阐明消化途径和雄激素调节之间的相互作用，并可能对前列腺癌有治疗意义。为申请人提供的培训环境非常好。导师舒斯丁·利亚姆博士研究雄激素调节和前列腺癌已有40多年，他的团队在该领域做出了几项开创性的贡献。本·梅癌症研究所（Ben May institute for Cancer Research）在前列腺癌研究方面有着悠久的传统，从诺贝尔奖得主哈金斯博士（Dr. Huggins）在前列腺癌治疗方面的工作开始。芝加哥大学有几个优秀的前列腺癌研究项目。有许多研究人员在前列腺癌领域工作，有许多核心设施，包括前列腺组织库。在周期调控、细胞凋亡、基因治疗等方面的良好训练，我有信心能够继续进行拟议的研究，并成功过渡到前列腺癌研究的前沿。NIH提供的资金支持将允许我完成我的培训，并在学术环境中启动我的载体和独立研究者。

the development of androgen-independence by prostate cancer cells is a major hurdle in the treatment of prostate cancer with conventional therapies. The major molecular defect is that the cancer cells fail to initiate programmed cell death (apoptosis) in response to various eupeptic stimuli. Recently we have found that over expression of bad, which is a pro-apoptotic molecule and a counterpart of BCL-2, includes apoptose in prostate cancer cells. In fact, androgen-independent LNCaP cells are even more sensitive to Bad-induced cell death than their androgen-dependent counterparts. Furthermore, subcellular localizations of Bad appear to be different in androgen-dependent and independent LNCaP cells. We hypothesize that Bad may play a critical role in the balance between cell survival and death in androgen-independent prostate cancers. We propose to investigate the molecular mechanisms underlying Bad-induced apoptosis in prostate cancer cells, as well as its relationship to the androgen-independent in vitro and in vivo. This work is novel as it will shed light on the interplay between an eupeptic pathway and androgen regulation and might have therapeutic implications for prostate cancer. The training environment for the applicant is excellent. Dr. Shustung Liam, the ,mentor, has been studying androgen regulation and prostate cancer for more tan 40 years and his group has made several ground breaking contributions to the field. The Ben May Institution for Cancer Research has long tradition for prostate cancer research, starting from the Noble Prize winning work of Dr. Huggins on treatment of prostate cancer. The University of Chicago has several excellent prostate cancer research programs. With many investigators and exports working in the field of prostate cancer and many Core facilities, including a prostate tissue bank. With the excellent training I have received in the fields of cycle regulation, apoptosis and gene therapy, I am confident that I will be able to pursue the proposed studies and make a successful transition into the front tier of prostate cancer research. The financial support provided by this NIH award will allow me to complete my training and to launch my carrier ad an independent investigator in an academic setting.