Membrane Microdomains in Prostate Cancer

描述（由申请人提供）：雄激素非依赖性前列腺癌（PCa）进展的信号转导机制仍然知之甚少。除了公知的雄激素在疾病的发展和进展中的作用之外，磷酸肌醇-3-激酶（PI 3 K）-Akt/蛋白激酶B（PK B）-> mTOR（雷帕霉素的哺乳动物靶蛋白）途径最近已被鉴定为前列腺肿瘤细胞生长和存活的重要调节剂。雄激素信号传导与其他信号传导途径，特别是PI 3 K/Akt/mTOR途径的交叉机制尚未明确描述，并且在许多方面存在争议。我们提出的证据表明，雄激素受体（AR）和PI 3 K/Akt信号之间的一个主要交叉点是在富含胆固醇的脂筏成分的质膜。我们提出了几条线的证据，这一结论，包括多个独立的观察，脂筏膜的Akt丝氨酸-苏氨酸激酶的直接调节的网站，证据表明，AR可以通过这一膜隔室，AR和Akt形成一个配体依赖性蛋白复合物优先在脂筏膜。从我们的初步数据中直接获得的一个重要假设是，雄激素通过AR与Akt的一种或多种磷酸化形式之间的直接相互作用来调节Akt，这表明筏膜是雄激素信号的重要分叉点。在本提案中，我们将通过追求以下具体目标来检验这一假设： 目标1.确定雄激素如何调节脂筏驻留Akt。 目标二。识别通过脂筏传递的信号通路，以及脂筏内存在的位于雄激素和其他AR激活剂下游的信号组分。 我们相信这些实验将提供实质性的新的洞察AR的作用，可溶性因子以外的雄激素存在于肿瘤环境中，和胆固醇丰富的膜在前列腺癌的进展。它们还旨在鉴定与PCa潜在相关的新信号蛋白，从而拓宽治疗干预的可能性。

DESCRIPTION (provided by applicant): The signal transduction mechanisms underlying progression to androgen-independent prostate cancer (PCa) are still poorly understood. In addition to the well-known role for androgen in development and progression of the disease, the phosphoinositide-3-kinase (PI3K) -Akt/protein kinase B (PKB) -> mTOR (mammalian target of rapamycin) pathway has recently been identified as an important regulator of prostate tumor cell growth and survival. The mechanisms of intersection of androgenic signaling with other signaling pathways, and in particular the PI3K/Akt/mTOR pathway, have not been clearly delineated, and in a number of respects are in dispute. We present evidence in this proposal that a major point of intersection between the androgen receptor (AR) and PI3K/Akt signaling is in the cholesterol-rich lipid raft component of the plasma membrane. We present several lines of evidence for this conclusion, including multiple independent observations that lipid raft membranes are sites of direct regulation of the Akt serine-threonine kinase, evidence that the AR can transit through this membrane compartment, and that AR and Akt form a ligand-dependent protein complex preferentially within lipid raft membranes. An important hypothesis obtained directly from our preliminary data is that androgen regulates Akt by direct interaction between AR and one or more phosphorylated forms of Akt, suggesting that the raft membrane is an important point of bifurcation for androgenic signals. In this proposal we will test this hypothesis by pursuing the following specific aims: Aim 1. Determine how androgen regulates lipid raft-resident Akt. Aim 2. Identify signaling pathways transmitted through lipid rafts, and signaling components present within rafts, that lie downstream of androgen and other AR activators. We believe these experiments will provide substantial new insight into the role of the AR, soluble factors other than androgen present in the tumor milieu, and cholesterol-rich membranes in PCa progression. They are also designed to identify new signaling proteins of potential relevance to PCa, thereby widening possibilities for therapeutic intervention.