Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Tokyo 171-8588, Japan.
Cancer Lett. 2010 Oct 1;296(1):17-26. doi: 10.1016/j.canlet.2010.03.010. Epub 2010 Apr 7.
The hypoxia-inducible factor (HIF) is a heterodimeric basic helix-loop-helix transcriptional factor and the activated HIF plays pivotal roles in various pathological conditions, including inflammation and cancer. HIF-1alpha overexpression has been observed in many common human cancers, including brain, breast, colon, lung, ovary, and prostate, and HIF-mediated genes, such as vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), and insulin-like growth factor (IGF)-1, are associated with tumor angiogenesis, metastasis, and invasion. Therefore, the pro-oncogenic protein HIF is a novel target of cancer therapy. We examined the effects of VEGFR inhibitors, AAL993, SU5416, and KRN633, on suppression of HIF-1alpha accumulation under the hypoxic condition. We found that VEGFR tyrosine kinase inhibitors, AAL993, SU5416, and KRN633, possess dual functions: inhibition of VEGFR signaling and HIF-1alpha expression under the hypoxic condition. The detailed mechanistic study indicated that SU5416 and KRN633 suppressed HIF-1alpha expression through inhibition of both Akt and ERK phosphorylation signaling pathways, whereas AAL993 suppressed HIF-1alpha expression through ERK inhibition without affecting Akt phosphorylation.
缺氧诱导因子 (HIF) 是一种异二聚体碱性螺旋-环-螺旋转录因子，激活的 HIF 在多种病理条件下发挥关键作用，包括炎症和癌症。在许多常见的人类癌症中都观察到 HIF-1α 的过表达，包括脑、乳腺、结肠、肺、卵巢和前列腺，并且 HIF 介导的基因，如血管内皮生长因子 (VEGF)、诱导型一氧化氮合酶 (iNOS) 和胰岛素样生长因子 (IGF)-1，与肿瘤血管生成、转移和侵袭有关。因此，致癌蛋白 HIF 是癌症治疗的新靶点。我们研究了 VEGFR 抑制剂 AAL993、SU5416 和 KRN633 在缺氧条件下抑制 HIF-1α 积累的作用。我们发现 VEGFR 酪氨酸激酶抑制剂 AAL993、SU5416 和 KRN633 具有双重功能：在缺氧条件下抑制 VEGFR 信号转导和 HIF-1α 表达。详细的机制研究表明，SU5416 和 KRN633 通过抑制 Akt 和 ERK 磷酸化信号通路抑制 HIF-1α 表达，而 AAL993 通过抑制 ERK 而不影响 Akt 磷酸化抑制 HIF-1α 表达。
