Untuning the tumor metabolic machine: HIF-α: pro- and antitumorigenic?
Untuning the tumor metabolic machine: HIF-α: pro- and antitumorigenic?
复制标题
DOI：
10.1038/nm.2865
复制
发表时间：
2012-07-06
期刊：
影响因子：
82.9
通讯作者：
Simon, M. Celeste
中科院分区：
文献类型：
--
作者：
Young, Regina M.;Simon, M. Celeste
实体瘤包含氧（O2）和营养限制的区域，这是由于其结构和功能异常的血管系统和癌细胞的快速增殖造成的。低氧诱导因子（HIF）介导了对低氧的主要转录反应，HIF刺激数百个基因的表达，促进细胞对低氧的适应。一些HIF靶基因调节参与肿瘤发生的过程，例如增加的葡萄糖摄取和糖酵解、血管生成、侵袭、转移和辐射抗性。此外，一些常见的致癌驱动因子，如mTORC 1和Ras，可增强HIF的活性。HIF以异二聚体的形式发挥功能，由稳定的β亚基和O2敏感的α亚基组成，在缺氧时聚集。在正常的O2条件下，HIF-α被代谢调节的脯氨酰羟化酶（PHDs）修饰，导致HIF-α亚基与von Hippel-Lindau（VHL）相关的E3泛素连接酶之间的物理相互作用，导致HIF-α快速周转。HIF-1α和HIF-2α这两种α亚基的亚型在缺氧反应中既有重叠的功能，也有不同的甚至是拮抗的作用1。诊断性肿瘤活检组织中的高HIF-1α和HIF-2α蛋白量与膀胱癌、脑癌、乳腺癌、结肠癌、宫颈癌、子宫内膜癌、头颈癌、肺癌、卵巢癌、胰腺癌、前列腺癌、直肠癌和胃癌的不良预后相关2。这些研究强烈支持开发用于癌症治疗的药理学HIF抑制剂。
Solid tumors contain regions of oxygen (O 2) and nutrient limitation resulting from their structurally and functionally abnormal vasculature and the rapid proliferation of cancer cells. The major transcriptional response to hypoxia is mediated by hypoxia-inducible factors (HIFs), which stimulate the expression of hundreds of genes that promote cellular adaptation to low O 2. Some of the HIF target genes regulate processes involved in tumorigenesis, such as increased glucose uptake and glycolysis, angiogenesis, invasion, metastasis and radiation resistance. Furthermore, a number of common oncogenic drivers, such as mTORC1 and Ras, enhance HIF activity.HIFs function as heterodimers, composed of stable β-subunits and O 2-sensitive α-subunits, which accumulate upon O 2 deprivation. In normal O 2 conditions, HIF-αs are modified by metabolically regulated prolyl hydroxylases (PHDs), leading to physical interactions between HIF-α subunits and the von Hippel-Lindau (VHL)-associated E3 ubiquitin ligase, resulting in rapid HIF-α turnover. Two well-characterized isoforms of the α-subunit, HIF-1α and HIF-2α, have both overlapping functions as well as divergent and even antagonistic roles in hypoxic responses 1. High HIF-1α and HIF-2α protein amounts in diagnostic tumor biopsies are correlated with poor prognosis in cancers of the bladder, brain, breast, colon, cervix, endometrium, head and neck, lung, ovary, pancreas, prostrate, rectum and stomach 2. These studies strongly support the development of pharmacological HIF inhibitors for cancer treatment.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Lu, Chao;Ward, Patrick S.;Kapoor, Gurpreet S.;Rohle, Dan;Turcan, Sevin;Abdel-Wahab, Omar;Edwards, Christopher R.;Khanin, Raya;Figueroa, Maria E.;Melnick, Ari;Wellen, Kathryn E.;O'Rourke, Donald M.;Berger, Shelley L.;Chan, Timothy A.;Levine, Ross L.;Mellinghoff, Ingo K.;Thompson, Craig B.
通讯作者：
Thompson, Craig B.
影响因子：
64.8
作者：
Koivunen, Peppi;Lee, Sungwoo;Duncan, Christopher G.;Lopez, Giselle;Lu, Gang;Ramkissoon, Shakti;Losman, Julie A.;Joensuu, Paivi;Bergmann, Ulrich;Gross, Stefan;Travins, Jeremy;Weiss, Samuel;Looper, Ryan;Ligon, Keith L.;Verhaak, Roel G. W.;Yan, Hai;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Semenza GL
通讯作者：
Semenza GL