Hypoxia and Anticancer Drug Action

缺氧与抗癌药物作用

• 批准号: 8637740
• 负责人: GARTH POWIS
• 金额: $ 40万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-14 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8637740
• 关键词: Adult; Angiogenic Factor; Antineoplastic Agents; Apoptosis; Binding; Blood Vessels; Cell Death; Clinical; Clinical Trials; DNA Binding; Development; Drug Targeting; Drug effect disorder; Drug resistance; Embryonic Development; Endoplasmic Reticulum; Environment; FGF2 gene; Genes; Goals; Grant; Growth; Health; Heat shock proteins; Human; Hypoxia; In Vitro; Investigation; Lead; Ligase; Maintenance; Malignant Neoplasms; Mediating; Metabolism; Molecular; Neoplasm Metastasis; Normal tissue morphology; Nuclear; Oxygen; Pathway interactions; Patients; Perfusion; Physiological Processes; Protein Biosynthesis; Protein Inhibition; Proteins; Radiation; Regulation; Resistance; Role; Small Interfering RNA; Solid Neoplasm; Staging; Stress; Therapeutic; Therapeutic Intervention; Tissues; Translations; Ubiquitination; Up-Regulation; analog; angiogenesis; base; biological adaptation to stress; cancer cell; cancer therapy; cell growth; chemotherapy; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; neoplastic cell; novel; outcome forecast; rapid growth; response; screening; stress protein; transcription factor; tumor; tumor growth; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Solid tumors exist in a stressed environment for cell growth. As even the smallest tumors grow they rapidly outstrip new blood vessel formation leading to poor perfusion and hypoxia. Genes induced by hypoxia allow the cancer cell to adapt to the hostile hypoxic environment by switching to anaerobic metabolism, decreasing overall protein synthesis, causing resistance to cell death, producing factors that increase the formation of new blood vessels from the existing vasculature (angiogenesis), and increased metastasis. Tumor cells also frequently develop constitutive upregulation of genes that regulate the hypoxic stress response. These constitutive and adaptive changes make tumors aggressive, resistant to radiation and chemotherapy, and lead to a poor patient prognosis. The hypoxic stress response is a normal physiological process employed in the early stages of embryogenesis but with a limited role in well perfused normal adult tissues. Although the changes result in aggressive, drug-resistant tumors they also provide an Achilles heel for selectively attacking the tumor, because without them the cancer cells will die. Thus, the hypothesis upon which our studies are based is that understanding the pathways that regulate the tumor's response to the stress of hypoxia and the consequences this has for tumor growth, will provide novel targets and the development of agents to selectively treat cancer. The most studied mechanism mediating the cancer cell's response to hypoxia is an increase in the levels of the hypoxia inducible factor-1 (HIF-11) transcription factor. We provide evidence for a new pathway of HIF-11 regulation by the endoplasmic reticulum (ER) unfolded protein response (UPR) that mediates the synthesis of HIF-11 and other stress proteins in hypoxia. We have also identified a novel oxygen independent pathway for HIF-11 degradation mediated by HAF/SART-1 which we have shown to be a novel E3 ubiquitin ligase for HIF-11. We will investigate the mechanisms and regulation of the HAF/SART-1-induced degradation of HIF-11 to provide novel targets for therapeutic intervention. There is ample clinical and experimental evidence for a HIF-11 independent mechanism for maintaining tumor growth in hypoxia. It is known that despite a general inhibition of protein translation during hypoxia the synthesis of HIF-11 and of other stress survival proteins is maintained or even increased. Understanding this mechanism could provide novel drug targets to inhibit the tumor's survival response to hypoxia. The overall goal of our studies is to understand mechanisms that contribute to the maintenance of tumor growth in hypoxia, involving both HIF-11 and other stress proteins that will provide new drug targets and therapeutic strategies for treating cancer.

描述(申请人提供)：实体瘤存在于细胞生长的压力环境中。即使是最小的肿瘤，其生长速度也会迅速超过新生血管的形成，从而导致血流灌注不足和缺氧。低氧诱导的基因允许癌细胞切换到无氧代谢，减少整体蛋白质合成，导致对细胞死亡的抵抗，产生增加现有血管系统新血管形成(血管生成)的因子，从而使癌细胞适应恶劣的低氧环境，并增加转移。肿瘤细胞还经常出现调节低氧应激反应的基因的结构性上调。这些结构性和适应性的变化使肿瘤具有侵袭性，对放射和化疗具有抵抗力，并导致患者预后不良。低氧应激反应是胚胎发育早期的正常生理过程，但在正常成人组织中的作用有限。尽管这些变化会导致侵袭性的、耐药的肿瘤，但它们也为选择性攻击肿瘤提供了一个致命弱点，因为没有它们，癌细胞就会死亡。因此，我们的研究所基于的假设是，了解调节肿瘤对低氧应激反应的途径及其对肿瘤生长的影响，将为选择性治疗癌症提供新的靶点和药物的开发。研究最多的介导癌细胞对低氧反应的机制是低氧诱导因子-1(HIF-11)转录因子水平的增加。我们通过内质网(ER)未折叠蛋白反应(UPR)调节HIF-11的新途径，该反应介导了HIF-11和其他应激蛋白在低氧中的合成。我们还发现了HIF/SART-1介导的HIF-11降解的一条新的不依赖氧的途径，这是一种新的HIF-11的E3泛素连接酶。我们将研究HAF/SART-1诱导HIF-11降解的机制和调控，为治疗干预提供新的靶点。有充分的临床和实验证据表明，HIF-11在低氧条件下维持肿瘤生长的独立机制。众所周知，尽管在低氧过程中蛋白质的翻译受到普遍的抑制，但HIF-11和其他应激生存蛋白的合成仍然保持甚至增加。了解这一机制可以为抑制肿瘤对低氧的生存反应提供新的药物靶点。我们研究的总体目标是了解在缺氧条件下维持肿瘤生长的机制，包括HIF-11和其他应激蛋白，这将为治疗癌症提供新的药物靶点和治疗策略。