Mitochondrial regulation of hypoxic signaling in tumor cells

描述（由申请人提供）：实体瘤的生长需要充足的氧气和营养供应。肿瘤细胞倾向于以超过由血管提供的氧和营养物的供应的速率增殖，导致低氧区域（缺氧，PO 2 =2-15 TORR）。因此，缺乏氧气的肿瘤细胞激活转录因子HIF-1以刺激新血管的形成（血管生成）。在分子水平上，缺氧诱导因子1（HIF-1）是糖酵解酶和VEGF基因的最具特征的转录调节因子。新血管对缺氧的反应是肿瘤生长和转移的关键步骤。尽管在理解低氧激活HIF-1的生物学重要性方面已经取得了很大进展，但细胞检测氧浓度降低（即氧感测）并启动导致低氧诱导的基因转录的信号传导途径的细胞内机制的基本问题仍然没有答案。我们建议测试的假设，线粒体作为氧传感器，通过增加产生的活性氧（ROS）内的电子传递链复合物III在缺氧。我们假设这些ROS作为信号分子激活p38 a MAPK信号通路，导致HIF-1依赖性肿瘤发生。缺氧的程度与血管生成和转移呈正相关，破译缺氧期间启动的细胞内信号通路将有助于我们了解肿瘤进展的基本方面，并为癌症治疗开发新的治疗方法。

DESCRIPTION (provided by applicant): The growth of solid tumors requires an adequate supply of oxygen and nutrients. Tumor cells tend to proliferate at a rate that exceeds the supply of oxygen and nutrients provided by blood vessels resulting in regions of low oxygen (hypoxia, PO2 =2-15 TORR). Accordingly, tumor cells starved for oxygen activate the transcription factor HIF-1 to stimulate the formation of new blood vessels (angiogenesis). At the molecular level, hypoxia-inducible factor 1 (HIF-1) is the best characterized transcriptional regulator of glycolytic enzymes and VEGF genes. The development of new blood vessels in response to hypoxia is a crucial step in both the growth and metastases of tumors. Although much progress in understanding the biological importance of hypoxic activation of HIF-1 has been made, the fundamental question of the intracellular mechanisms by which cells detect the decrease in oxygen concentration (i.e. oxygen sensing) and initiate signaling pathways that result in hypoxia induced gene transcription remains unanswered. We propose to test the hypothesis that mitochondria serve as oxygen sensors by increasing the generation of reactive oxygen species (ROS) within complex III of the electron transport chain during hypoxia. We hypothesize these ROS serve as signaling molecules to activate the p38a MAPK signaling pathway resulting in HIF-1 dependent tumorigenesis. The degree of hypoxia correlates positively with angiogenesis and metastases, deciphering the intracellular signaling pathways initiated during hypoxia will contribute to our understanding of the basic aspects of tumor progression and to the development of new therapeutic approaches for cancer treatment.