Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species.
Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species.
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DOI：
10.1128/mcb.00483-09
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发表时间：
2009-08
影响因子：
5.3
通讯作者：
Neckers L
中科院分区：
文献类型：
--
作者：
Sudarshan S;Sourbier C;Kong HS;Block K;Valera Romero VA;Yang Y;Galindo C;Mollapour M;Scroggins B;Goode N;Lee MJ;Gourlay CW;Trepel J;Linehan WM;Neckers L
遗传性平滑肌瘤病和肾癌(HLRCC)是一种遗传性癌症综合征，与富马酸水合酶(FH)编码三羧酸循环酶基因的双等位基因失活有关。HLRCC患者有患皮肤和子宫肌瘤以及侵袭性肾癌的风险。假性低氧驱动--尽管氧分压正常，细胞低氧反应通路的异常激活--被认为是这种肿瘤的一个可能的发病机制。假缺氧要求缺氧诱导转录因子α亚基(HIF-1α)的氧非依赖性稳定。在常氧条件下，缺氧诱导因子-1α的脯氨酸羟化使其能够识别并随后靶向于蛋白酶体的降解。在这里，我们证明了在HLRCC来源的细胞系中FH的失活突变导致葡萄糖介导的细胞活性氧物种(ROS)的产生和ROS依赖的HIF-1α的稳定。此外，我们还证明了在永生化的肾上皮细胞中稳定地敲除FH导致了ROS依赖的HIF-1α的稳定。这些数据表明，HLRCC中存在的专性糖酵解开关对于通过产生ROS稳定HIF至关重要。
Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an inherited cancer syndrome linked to biallelic inactivation of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH). Individuals with HLRCC are at risk to develop cutaneous and uterine leiomyomas and an aggressive form of kidney cancer. Pseudohypoxic drive - the aberrant activation of cellular hypoxia response pathways despite normal oxygen tension - is considered to be a likely mechanism underlying the etiology of this tumor. Pseudohypoxia requires the oxygen-independent stabilization of the alpha subunit of hypoxia-inducible transcription factor (HIF-1α). Under normoxic conditions, proline hydroxylation of HIF-1α permits VHL recognition and subsequent targeting for proteasomal degradation. Here we demonstrate that inactivating mutations of FH in an HLRCC-derived cell line result in glucose-mediated generation of cellular reactive oxygen species (ROS) and ROS-dependent HIF-1α stabilization. Additionally, we demonstrate that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1α stabilization. These data reveal that the obligate glycolytic switch present in HLRCC is critical to HIF stabilization via ROS generation.