乳腺癌中谷氨酸对缺氧诱导因子的旁分泌诱导作用：EglN1感受半胱氨酸。
Paracrine Induction of HIF by Glutamate in Breast Cancer: EglN1 Senses Cysteine.
作者信息
Briggs Kimberly J, Koivunen Peppi, Cao Shugeng, Backus Keriann M, Olenchock Benjamin A, Patel Hetalben, Zhang Qing, Signoretti Sabina, Gerfen Gary J, Richardson Andrea L, Witkiewicz Agnieszka K, Cravatt Benjamin F, Clardy Jon, Kaelin William G
机构信息
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA 02215, USA.
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
出版信息
Cell. 2016 Jun 30;166(1):126-39. doi: 10.1016/j.cell.2016.05.042.
Abstract
The HIF transcription factor promotes adaptation to hypoxia and stimulates the growth of certain cancers, including triple-negative breast cancer (TNBC). The HIFα subunit is usually prolyl-hydroxylated by EglN family members under normoxic conditions, causing its rapid degradation. We confirmed that TNBC cells secrete glutamate, which we found is both necessary and sufficient for the paracrine induction of HIF1α in such cells under normoxic conditions. Glutamate inhibits the xCT glutamate-cystine antiporter, leading to intracellular cysteine depletion. EglN1, the main HIFα prolyl-hydroxylase, undergoes oxidative self-inactivation in the absence of cysteine both in biochemical assays and in cells, resulting in HIF1α accumulation. Therefore, EglN1 senses both oxygen and cysteine.
摘要
缺氧诱导因子（HIF）转录因子可促进细胞适应缺氧环境，并刺激某些癌症的生长，包括三阴性乳腺癌（TNBC）。在常氧条件下，HIFα亚基通常会被EglN家族成员进行脯氨酰羟基化，导致其迅速降解。我们证实，TNBC细胞会分泌谷氨酸，发现在常氧条件下，谷氨酸对于此类细胞中HIF1α的旁分泌诱导作用而言既是必要的也是充分的。谷氨酸会抑制xCT谷氨酸-胱氨酸反向转运体，导致细胞内半胱氨酸耗竭。在生化分析和细胞实验中，主要的HIFα脯氨酰羟化酶EglN1在缺乏半胱氨酸的情况下会发生氧化自失活，从而导致HIF1α积累。因此，EglN1既能感知氧气又能感知半胱氨酸。
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