Mitochondrial regulation of hypoxic signaling in tumor cells

描述（申请人提供）：实体瘤的生长需要足够的氧气和营养供应。肿瘤细胞倾向于以超过血管提供的氧气和营养供应的速度增殖，导致低氧区域（缺氧，PO2 =2-15 TORR）。因此，缺氧的肿瘤细胞激活转录因子HIF-1来刺激新血管的形成（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基因的转录调节因子。在缺氧条件下，新生血管的形成是肿瘤生长和转移的关键步骤。尽管在了解缺氧激活HIF-1的生物学重要性方面取得了很大进展，但细胞检测氧浓度降低（即氧感应）并启动导致缺氧诱导基因转录的信号通路的细胞内机制的基本问题仍未得到解答。我们提议通过在缺氧时增加电子传递链复合体III内活性氧（ROS）的产生来验证线粒体作为氧传感器的假设。我们假设这些ROS作为信号分子激活p38a MAPK信号通路，导致HIF-1依赖性肿瘤发生。缺氧程度与血管生成和转移呈正相关，破译缺氧时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，并有助于开发新的治疗方法。

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.