Authors' Affiliations: Departments of Radiation Oncology,Surgery, Pathology, and Radiology, Duke University Medical Center, Durham; Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Radiology, Mayo Clinic, Rochester, Minnesota; Department of Radiation Oncology, Stanford University, Stanford, California; and Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Cancer Res. 2013 Oct 15;73(20):6230-42. doi: 10.1158/0008-5472.CAN-12-1345. Epub 2013 Aug 19.
Hypoxia-inducible factor 1 (HIF-1) is a master transcription factor that controls cellular homeostasis. Although its activation benefits normal tissue, HIF-1 activation in tumors is a major risk factor for angiogenesis, therapeutic resistance, and poor prognosis. HIF-1 activity is usually suppressed under normoxic conditions because of rapid oxygen-dependent degradation of HIF-1α. Here, we show that, under normoxic conditions, HIF-1α is upregulated in tumor cells in response to doxorubicin, a chemotherapeutic agent used to treat many cancers. In addition, doxorubicin enhanced VEGF secretion by normoxic tumor cells and stimulated tumor angiogenesis. Doxorubicin-induced accumulation of HIF-1α in normoxic cells was caused by increased expression and activation of STAT1, the activation of which stimulated expression of iNOS and its synthesis of nitric oxide (NO) in tumor cells. Mechanistic investigations established that blocking NO synthesis or STAT1 activation was sufficient to attenuate the HIF-1α accumulation induced by doxorubicin in normoxic cancer cells. To our knowledge, this is the first report that a chemotherapeutic drug can induce HIF-1α accumulation in normoxic cells, an efficacy-limiting activity. Our results argue that HIF-1α-targeting strategies may enhance doxorubicin efficacy. More generally, they suggest a broader perspective on the design of combination chemotherapy approaches with immediate clinical impact.
缺氧诱导因子 1（HIF-1）是一种控制细胞内稳态的主要转录因子。尽管其激活对正常组织有益，但肿瘤中的 HIF-1 激活是血管生成、治疗抵抗和预后不良的主要危险因素。由于 HIF-1α 的快速氧依赖性降解，HIF-1 在常氧条件下通常被抑制。在这里，我们表明，在常氧条件下，多柔比星（一种用于治疗多种癌症的化疗药物）会导致肿瘤细胞中的 HIF-1α 上调。此外，多柔比星增强了常氧肿瘤细胞中 VEGF 的分泌，并刺激了肿瘤血管生成。常氧细胞中 HIF-1α 的多柔比星诱导积累是由 STAT1 的表达和激活增加引起的，其激活刺激了肿瘤细胞中 iNOS 的表达及其合成的一氧化氮（NO）。机制研究表明，阻断 NO 合成或 STAT1 激活足以减弱常氧癌细胞中多柔比星诱导的 HIF-1α 积累。据我们所知，这是第一个报道化疗药物可以诱导常氧细胞中 HIF-1α 积累的报告，这是一种疗效受限的活性。我们的结果表明，针对 HIF-1α 的策略可能会增强多柔比星的疗效。更广泛地说，它们为设计具有直接临床影响的联合化疗方法提供了更广泛的视角。
