Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer.
Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer.
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DOI：
10.1038/oncsis.2016.13
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发表时间：
2016-03-14
期刊：
影响因子：
6.2
通讯作者：
Cuvillier O
中科院分区：
文献类型：
--
作者：
Bouquerel P;Gstalder C;Müller D;Laurent J;Brizuela L;Sabbadini RA;Malavaud B;Pyronnet S;Martineau Y;Ader I;Cuvillier O
鞘氨醇激酶-1/鞘氨醇1-磷酸（SphK 1/S1 P）信号通路在多种细胞系中调节经典转录因子低氧诱导型HIF-1α的表达。HIF-2α也经常在实体瘤中过表达，但其作用主要在透明细胞肾细胞癌（ccRCC）中研究，这是最常见的肾癌形式，其中HIF-2α已被确定为更具侵袭性疾病的驱动因素。在这项研究中，SphK 1/S1 P信号转导在包括ccRCC细胞在内的各种癌细胞模型中对HIF-2α的作用进行了研究。在缺氧条件下或在缺乏功能性von Hippel-Lindau（VHL）基因并表达高水平HIF-2α的ccRCC中，SphK 1活性通过磷脂酶D（PLD）驱动机制控制HIF-2α表达和转录活性。SphK 1沉默促进了不依赖VHL的HIF-2α表达和活性的丧失，并降低了ccRCC中的细胞增殖。重要的是，SphK 1的下调与ccRCC中Akt和mTOR信号传导受损相关。利用中和细胞外S1 P的单克隆抗体，我们发现抑制S1 P细胞外信号传导可以阻断ccRCC细胞系中HIF-2α的积累，当S1 P转运蛋白Spns 2或S1 P受体1（S1 P1）沉默时，这种作用可以模拟。在这里，我们报告了第一个证据，即SphK 1/S1 P信号通路在不同的癌细胞谱系中调节转录因子缺氧诱导的HIF-2α，特别是ccRCC，其中HIF-2α已被确定为更具侵袭性疾病的驱动因素。这些发现表明，SphK 1/S1 P信号传导可能是ccRCC中HIF-2α表达的典型调节因子，支持其抑制作为一种治疗策略，可能有助于降低ccRCC中HIF-2活性。
The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway has been reported to modulate the expression of the canonical transcription factor hypoxia-inducible HIF-1α in multiple cell lineages. HIF-2α is also frequently overexpressed in solid tumors but its role has been mostly studied in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, where HIF-2α has been established as a driver of a more aggressive disease. In this study, the role of SphK1/S1P signaling with regard to HIF-2α was investigated in various cancer cell models including ccRCC cells. Under hypoxic conditions or in ccRCC lacking a functional von Hippel-Lindau (VHL) gene and expressing high levels of HIF-2α, SphK1 activity controls HIF-2α expression and transcriptional activity through a phospholipase D (PLD)-driven mechanism. SphK1 silencing promotes a VHL-independent HIF-2α loss of expression and activity and reduces cell proliferation in ccRCC. Importantly, downregulation of SphK1 is associated with impaired Akt and mTOR signaling in ccRCC. Taking advantage of a monoclonal antibody neutralizing extracellular S1P, we show that inhibition of S1P extracellular signaling blocks HIF-2α accumulation in ccRCC cell lines, an effect mimicked when the S1P transporter Spns2 or the S1P receptor 1 (S1P1) is silenced. Here, we report the first evidence that the SphK1/S1P signaling pathway regulates the transcription factor hypoxia-inducible HIF-2α in diverse cancer cell lineages notably ccRCC, where HIF-2α has been established as a driver of a more aggressive disease. These findings demonstrate that SphK1/S1P signaling may act as a canonical regulator of HIF-2α expression in ccRCC, giving support to its inhibition as a therapeutic strategy that could contribute to reduce HIF-2 activity in ccRCC.