HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs.
HIF-1-mediated metabolic reprogramming reduces ROS levels and facilitates the metastatic colonization of cancers in lungs.
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DOI：
10.1038/srep03793
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发表时间：
2014-01-23
影响因子：
4.6
通讯作者：
Harada H
中科院分区：
文献类型：
--
作者：
Zhao T;Zhu Y;Morinibu A;Kobayashi M;Shinomiya K;Itasaka S;Yoshimura M;Guo G;Hiraoka M;Harada H
低氧诱导因子1（HIF-1）与肿瘤的远处转移有关，但其在肿瘤转移过程中的作用尚未完全阐明。在本研究中，我们证明，癌细胞瞬时上调HIF-1的活性在其转移性定植后，在肺外渗缺氧非依赖性和活性氧（ROS）依赖性的方式。瞬时激活诱导乳酸脱氢酶A的表达和丙酮酸脱氢酶E1 α亚基的磷酸化，这表明葡萄糖代谢途径从线粒体氧化磷酸化到无氧糖酵解和乳酸发酵的重编程。给予HIF-1抑制剂YC-1抑制了这种重编程，增加了肿瘤内ROS水平，并最终抑制了转移性肺肿瘤的形成。这些结果表明，HIF-1介导的代谢重编程是负责转移性癌症的生存期间，他们在肺部定植减少细胞毒性ROS水平，因此，它的阻断HIF-1抑制剂是一个合理的策略，以防止肿瘤转移。
Hypoxia-inducible factor 1 (HIF-1) has been associated with distant tumor metastasis; however, its function in multiple metastatic processes has not yet been fully elucidated. In the present study, we demonstrated that cancer cells transiently upregulated HIF-1 activity during their metastatic colonization after extravasation in the lungs in hypoxia-independent and reactive oxygen species (ROS)-dependent manners. Transient activation induced the expression of lactate dehydrogenase A and phosphorylation of the E1α subunit of pyruvate dehydrogenase, which indicated the reprogramming of glucose metabolic pathways from mitochondrial oxidative phosphorylation to anaerobic glycolysis and lactic acid fermentation. The administration of the HIF-1 inhibitor, YC-1, inhibited this reprogramming, increased intratumoral ROS levels, and eventually suppressed the formation of metastatic lung tumors. These results indicate that HIF-1-mediated metabolic reprogramming is responsible for the survival of metastatic cancers during their colonization in lungs by reducing cytotoxic ROS levels; therefore, its blockade by HIF-1-inhibitors is a rational strategy to prevent tumor metastasis.
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影响因子：
8
作者：
Semenza, G. L.
通讯作者：
Semenza, G. L.
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
8.8
作者：
Harada, H.;Itasaka, S.;Zhu, Y.;Zeng, L.;Xie, X.;Morinibu, A.;Shinomiya, K.;Hiraoka, M.
通讯作者：
Hiraoka, M.
影响因子：
13.8
作者：
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通讯作者：
Semenza GL
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
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