Direct conversion of osteosarcoma to adipocytes by targeting TNIK
Direct conversion of osteosarcoma to adipocytes by targeting TNIK
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DOI：
10.1172/jci.insight.137245
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发表时间：
2021-02-08
期刊：
影响因子：
8
通讯作者：
Yamada, Tesshi
中科院分区：
文献类型：
--
作者：
Hirozane, Toru;Masuda, Mari;Yamada, Tesshi
骨肉瘤（OS）是一种侵袭性间充质肿瘤，目前尚无分子靶向治疗方法。我们之前已经发现TRAF2-和nck相互作用蛋白激酶（TNIK）是Wnt信号靶基因反激活的重要因素，并表明其抑制导致大肠癌干细胞的根除。Wnt信号在OS发病机制中的作用已被证实。本研究的目的是研究TNIK作为OS治疗靶点的潜力。RNA干扰或药物抑制TNIK抑制OS细胞的增殖。转录组分析表明，TNIK的一种小分子抑制剂上调了参与OS细胞代谢的基因的表达，下调了维持干细胞表型所必需的转录因子。代谢组学分析显示，这种TNIK抑制剂在OS细胞中将代谢网络从碳通量转向脂质积累。通过体外和体内OS模型，我们证实TNIK抑制消除了OS干细胞表型，同时通过诱导PPAR γ驱动OS细胞转化为脂肪细胞li Ice细胞。关于临床实践中潜在的治疗靶点，TNIK在OS细胞系和临床标本中被证实处于活跃状态。根据这些发现，我们得出结论，TNIK可作为治疗OS的潜在靶点，影响细胞命运的决定。
Osteosarcoma (OS) is an aggressive mesenchymal tumor for which no molecularly targeted therapies are available. We have previously identified TRAF2- and NCK-interacting protein kinase (TNIK) as an essential factor for the transactivation of Wnt signal target genes and shown that its inhibition leads to eradication of colorectal cancer stem cells. The involvement of Wnt signaling in the pathogenesis of OS has been implicated. The aim of the present study was to examine the potential of TNIK as a therapeutic target in OS. RNA interference or pharmacological inhibition of TNIK suppressed the proliferation of OS cells. Transcriptome analysis suggested that a small-molecule inhibitor of TNIK upregulated the expression of genes involved in OS cell metabolism and down regulated transcription factors essential for maintaining the stem cell phenotype. Metabolome analysis revealed that this TNIK inhibitor redirected the metabolic network from carbon flux toward lipid accumulation in OS cells. Using in vitro and in vivo OS models, we confirmed that TNIK inhibition abrogated the OS stem cell phenotype, simultaneously driving conversion of OS cells to adipocyte-li Ice cells through induction of PPAR gamma. In relation to potential therapeutic targeting in clinical practice, TNIK was confirmed to be in an active state in OS cell lines and clinical specimens. From these findings, we conclude that TNIK is applicable as a potential target for treatment of OS, affecting cell fate determination.