Targeting Sterol Gene SC4MOL and EGFR as Synergistic Anti-Cancer Strategy

摘要 表皮生长因子受体(Egfr)已被广泛用作癌症阻断的靶点。 心理治疗。在正常的上皮细胞中，配体诱导激活的受体内化及其分选 溶酶体的降解是EGFR信号转导的限制机制。这种脱敏过程是 通常被癌细胞绕过以促进其生长和存活，即使在EGFR存在的情况下也是如此 信号转导抑制剂。我们已经确定了类固醇生物合成途径的一个新角色来影响这一点。 回收工艺，可显著提高EGFR靶向抑制剂的效果。沉默的声音 SC4MOL(类固醇C4-甲基氧化物酶)可显著增加肿瘤细胞对EGFR抑制剂的敏感性 基于网络引导的siRNA筛选(AstSaturov，2010)。我们已经确定SC4MOL和a 功能连锁的伙伴蛋白NSDHL(NADP依赖的类固醇脱氢酶)是阴性的 EGFR及其家族成员ErbB2和ErbB3从质膜向细胞膜转运的调节 用来毁灭的溶酶体。我们的中心假设是类固醇生物合成途径的代谢受阻 会加速受体降解，从而在体外抑制EGFR信号；在NSDHL条件基因敲除中 老鼠，这将限制上皮癌的发生。我们的直接目标是验证一个新的代谢目标 癌症治疗涉及这些以前未知的基因在远端的类固醇生物合成途径。 随着强大的合作者团队的组建，我们提出了以下三个具体目标： 目的1.探讨雌激素生物合成中EGFR信号转导的基因调控机制 路径。根据初步数据和补充的生物信息学分析，我们假设 阻断SC4MOL和NSDHL导致EGFR贩运改变，从而加速EGFR在 溶酶体。 目的2.确定联合靶向SC4MOL和EGFR在肿瘤移植瘤中的价值。 根据我们的初步体外数据，我们认为SC4MOL的shRNA沉默将增加 肿瘤移植瘤对EGFR阻断的反应。 目的3.研究体内类固醇途径对EGFR信号转导和易感性的影响 致癌物质。我们假设上皮性NSDHL缺乏症的EGFR拮抗作用将限制 H-RAS依赖或非依赖致癌。 这一提议意义重大，因为它将从根本上为新陈代谢提供新的知识 类固醇调节必要的癌症受体的信号活性，如EGFR。我们相信 SC4MOL和NSDHL等类固醇途径靶点的药理抑制可能会导致癌症 化疗和化学预防是一类全新的药物。

Abstract Epidermal growth factor receptor (EGFR) has been heavily exploited as a target for blockade in cancer therapy. In normal epithelial cells, ligand-induced internalization of activated receptors and their sorting for degradation in lysosomes is the limiting mechanism for EGFR signaling. This desensitization process is commonly circumvented by cancer cells to promote their growth and survival even in the presence of EGFR signaling inhibitors. We have identified a novel role for the sterol biosynthesis pathway to influence this recycling process which could significantly improve the efficacy of EGFR-targeting inhibitors. Silencing of SC4MOL (sterol C4-methyl oxidase-like) significantly sensitizes tumor cells to EGFR inhibitors using a network-guided siRNA-based screen (Astsaturov, 2010). We have determined that SC4MOL and a functionally linked partner protein, NSDHL (NADP-dependent steroid dehydrogenase-like), are negative regulators of trafficking of EGFR and its family members ErbB2 and ErbB3 from the plasma membrane to the lysosome for destruction. Our central hypothesis is that metabolic blockade of the sterol biosynthesis pathway will accelerate receptor degradation and thus suppress EGFR signaling in vitro; in NSDHL conditional knockout mice, this will limit epithelial carcinogenesis. Our immediate objective is to validate a new metabolic target for cancer therapy involving these previously unexplored genes in the distal sterol biosynthesis pathway. With the strong team of collaborators assembled, we propose the following 3 specific Aims: Aim 1. Investigate the mechanism of EGFR signaling regulation by genes in the sterol biosynthesis pathway. On the basis of preliminary data and complementary bioinformatic analysis, we hypothesize that blockade of SC4MOL and NSDHL causes altered EGFR trafficking that accelerates EGFR degradation in lysosomes. Aim 2. Determine the value of combined targeting of SC4MOL and EGFR in tumor xenografts. Based on our preliminary in vitro data, we propose that shRNA silencing of SC4MOL will increase the response of tumor xenografts to EGFR blockade. Aim 3. Investigate in vivo effects of sterol pathway on EGFR signaling and susceptibility to carcinogens. We hypothesize that the EGFR-antagonistic effects of the epithelial NSDHL deficiency will limit the H-Ras-dependent or -independent carcinogenesis. This proposal is significant because it will provide fundamentally new knowledge on how the metabolism of sterols regulates signaling activity of essential cancer receptors such as EGFR. We believe that pharmacological inhibition of sterol pathway targets such as SC4MOL and NSDHL has the potential for cancer chemotherapy and chemoprevention as an entirely novel class of agents.