Molecular Mechanisms of Insulin Signaling in the Malignant Cell Transformation

恶性肿瘤细胞转化中胰岛素信号传导的分子机制

• 批准号: 236984515
• 负责人: Dr. René Thierbach
• 金额: --
• 依托单位: Institut für Ernährungswissenschaften
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/236984515?language=en
• 关键词: Molecular; Mechanisms; Insulin; Signaling; Malignant

Increased cancer incidence in states of elevated blood glucose or diabetes mellitus suggest an influence of metabolic changes onto cancer development. Dysregulations of the insulin/IGF1-axis or related pathways may cause changes in metabolism as well as cancer-related processes like proliferation and apoptosis. The elucidation of these potentially causal relations would give benefits for cancer therapies and cancer prevention and is aim of scientific works since several years.In preliminary experiments we have shown that pharmacological inhibition using the insulin/IGF1-receptor inhibitor OSI-906 prevents the malignant transformation of cells. This inhibitor-mediated protective mechanism is highly effective and may help to elucidate the causal relations between changed energy metabolism an malignant transformation of cells.The aims of the current proposal are to apply these cell-based results onto the in vivo-situation by studying appropriate rodent carcinogenicity models to elucidate the underlying protective mechanisms on a spatiotemporal molecular level, and to subsequently apply these mechanisms to additional transforming influences.The anticipated results will enable insights into molecular mechanisms of the insulin/IFG1 signaling during tumor developmental processes as well as therapeutic approaches on existing tumors by use of inhibitors of the downstream PI3K/Akt signaling pathways. This project may help to interpret the action of insulin signaling during cancer development in different tissues. Modulation of these signaling events via pharmacological or dietary interventions may promote efficacy of pre-existing cancer therapies. Due to the fact that most cancer therapeutic treatments exert genotoxic defects also in healthy tissues it seems feasible that concomitant modulation of insulin/IGF1 signaling may in addition have protective effects.Anticipated results from this proposal will elucidate molecular links between altered energy metabolism and molecular events in malignant transformation directly impacting both cancer prevention as well as cancer therapy.

在血糖升高或糖尿病状态下癌症发病率增加表明代谢变化对癌症发展的影响。胰岛素/IGF 1轴或相关途径的失调可能会导致代谢以及癌症相关过程（如增殖和凋亡）的变化。阐明这些潜在的因果关系将有利于癌症的治疗和癌症的预防，是多年来科学工作的目标。在初步实验中，我们已经表明，使用胰岛素/IGF 1受体抑制剂OSI-906的药理学抑制可以防止细胞的恶性转化。这一由通道介导的保护机制非常有效，可能有助于阐明能量代谢改变与细胞恶性转化之间的因果关系。本研究的目的是将这些基于细胞的结果应用于体内情况，通过研究合适的啮齿动物致癌模型，在时空分子水平上阐明潜在的保护机制，预期的结果将有助于深入了解肿瘤发生过程中胰岛素/IFG 1信号传导的分子机制，以及通过使用下游PI 3 K/Akt信号传导途径的抑制剂对现有肿瘤的治疗方法。该项目可能有助于解释胰岛素信号在不同组织中癌症发展过程中的作用。通过药理学或饮食干预调节这些信号传导事件可能会促进既存癌症治疗的疗效。由于事实上，大多数癌症的治疗方法也发挥遗传毒性缺陷，在健康组织似乎可行的，伴随调制的胰岛素/IGF 1信号可能另外具有protective effects.Anticipated结果从这个建议将阐明改变能量代谢和分子之间的联系，在恶性转化的分子事件直接影响癌症的预防以及癌症的治疗。