Membrane Microdomains in Prostate Cancer

描述(由申请人提供)：进展为雄激素非依赖性前列腺癌(PCa)的信号转导机制仍然知之甚少。除了众所周知的雄激素在前列腺癌发生发展中的作用外，最近还发现磷脂酰肌醇-3-激酶(PI3K)-Akt/蛋白激酶B(PKB)-mTOR(雷帕霉素的哺乳动物靶标)通路是前列腺肿瘤细胞生长和存活的重要调节因子。雄激素信号通路与其他信号通路，特别是PI3K/Akt/mTOR通路的交叉机制还没有清楚地描述出来，在许多方面也存在争议。我们提出的证据表明，雄激素受体(AR)和PI3K/Akt信号之间的一个主要交叉点是在质膜的富含胆固醇的脂筏成分中。我们为这一结论提供了几条证据，包括多个独立的观察结果，即脂筏膜是Akt丝氨酸-苏氨酸激酶的直接调节部位，证据表明AR可以通过这个膜室，以及AR和Akt优先在脂筏膜内形成配体依赖的蛋白质复合体。直接从我们的初步数据中得到的一个重要假设是，雄激素通过AR与一种或多种Akt的磷酸化形式之间的直接相互作用来调节Akt，这表明RAFT膜是雄激素信号的一个重要分叉点。在这项提议中，我们将通过追求以下具体目标来检验这一假设： 目的1.确定雄激素对脂筏驻留Akt的调节作用。 目的2.确定通过脂筏传递的信号通路，以及存在于脂筏中的位于雄激素和其他AR激活剂下游的信号成分。 我们相信，这些实验将为AR、存在于肿瘤环境中的雄激素以外的可溶性因子以及富含胆固醇的膜在前列腺癌进展中的作用提供实质性的新见解。它们还被设计用来识别与PCa潜在相关的新的信号蛋白，从而扩大治疗干预的可能性。

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.