期刊
CANCER RESEARCH
卷 68, 期 20, 页码 8635-8642出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-0917
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资金
- Centre National de la Recherche Scientifique, Ligue Nationale Contre le Cancer, the Association pour la Recherche sur les Tumeurs de la Prostate
Here, we provide the first evidence that sphingosine kinase I (SphKI), an oncogenic lipid kinase balancing the intracellular level of key signaling sphingolipids, modulates the transcription factor hypoxia inducible factor la (HIF-1 alpha), master regulator of hypoxia. SpbKI activity is stimulated under low oxygen conditions and regulated by reactive oxygen species. The SphK1-dependent stabilization of HIF-1a levels is mediated by the Akt/glycogen synthase kinase-3 beta signaling pathway that prevents its von Hippel-Lindau protein-mediated degradation by the proteasome. The pharmacologic and RNA silencing inhibition of SphK1 activity prevents the accumulation of HIF-1 alpha and its transcriptional activity in several human cancer cell lineages (prostate, brain, breast, kidney, and lung), suggesting a canonical pathway. Therefore, we propose that SphK1 can act as a master regulator for hypoxia, giving support to its inhibition as a valid strategy to control tumor hypoxia and its molecular consequences. [Cancer Res 2008;68(20):8635-42]
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