PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells
PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells
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PSAT1 调节细胞周期蛋白 D1 降解并维持非小细胞肺癌细胞的增殖。
DOI：
10.1002/ijc.29150
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发表时间：
2015-02-15
影响因子：
6.4
通讯作者：
Guan, Hongyu
中科院分区：
文献类型：
--
作者：
Yang, Yi;Wu, Jueheng;Guan, Hongyu
一碳代谢途径中的多个节点在癌细胞生长和肿瘤发生中起着重要的调节作用。然而，代谢酶在调节与肿瘤细胞生长和存活相关的信号传导途径中的特定生物学功能仍不清楚。我们目前的研究发现，磷酸丝氨酸氨基转移酶1（PSAT 1），一种催化丝氨酸生物合成的酶，在非小细胞肺癌（NSCLC）中显著上调，并参与E2 F活性的调节。功能丧失和获得实验表明，PSAT 1促进细胞周期进程，细胞增殖和肿瘤发生。机制研究表明，PSAT 1升高导致cyclin D1降解抑制，随后Rb-E2 F通路活性改变，从而促进NSCLC细胞的G1进展和增殖。此外，磷酸化的细胞周期蛋白D1在苏氨酸286 GSK-3所需的PSAT 1诱导的细胞周期蛋白D1降解的阻断。我们还发现p70 S6 K的活性介导了PSAT 1对GSK-3磷酸化和cyclin D1降解的影响。我们进一步确定PSAT 1在NSCLC中过表达，并预测患有该疾病的患者的不良临床结果。相关分析显示，PSAT 1表达与磷酸化GSK-3、cyclin D1和磷酸化Rb水平呈正相关。这些发现揭示了E2 F的组成性激活机制，通过该机制，NSCLC中发生无限制的细胞周期进展，并可能代表预后生物标志物和治疗靶点。代谢酶在肿瘤发生中起着关键的调节作用，尽管它们对肿瘤细胞生长和存活的具体贡献尚不清楚。这份报告是第一个证明磷酸丝氨酸氨基转移酶1（PSAT 1），一种参与丝氨酸生物合成的酶，在非小细胞肺癌（NSCLC）中过表达。升高的PSAT 1似乎通过促进细胞周期进展来增强NSCLC细胞的增殖，这种作用与抑制细胞周期蛋白D1降解和改变Rb-E2 F途径的活性有关。结果表明，NSCLC中不受限制的细胞周期进展与PSAT 1上调和E2 F的组成性激活有关。
Multiple nodes in the one-carbon metabolism pathway play important regulatory roles in cancer cell growth and tumorigenesis. The specific biological functions of metabolic enzymes in regulating the signaling pathways that are associated with tumor cell growth and survival, however, remain unclear. Our current study found that phosphoserine aminotransferase 1 (PSAT1), an enzyme catalyzing serine biosynthesis, was significantly up-regulated in non-small cell lung cancer (NSCLC) and was involved in the regulation of E2F activity. Loss- and gain-of-function experiments demonstrated that PSAT1 promoted cell cycle progression, cell proliferation and tumorigenesis. Mechanistic study suggested that elevated PSAT1 led to inhibition of cyclin D1 degradation and subsequently an alteration in Rb-E2F pathway activity, which in turn enhanced G1 progression and proliferation of NSCLC cells. Moreover, phosphorylation of cyclin D1 at threonine 286 by GSK-3 was required for PSAT1-induced blockage of cyclin D1 degradation. We also found that the activity of p70S6K mediated the effects of PSAT1 on GSK-3 phosphorylation and cyclin D1 degradation. We further identified that PSAT1 was over-expressed in NSCLC and predicted poor clinical outcome of patients with the disease. Correlation analysis showed that PSAT1 expression positively correlated with the levels of phosphorylated GSK-3, cyclin D1 and phosphorylated Rb in NSCLC primary tumors. These findings uncover a mechanism for constitutive activation of E2F via which unrestrained cell cycle progression occurs in NSCLC and may represent a prognostic biomarker and therapeutic target.What's new? Metabolic enzymes play key regulatory roles in tumorigenesis, though their specific contributions to tumor cell growth and survival are unclear. This report is the first to demonstrate that phosphoserine aminotransferase 1 (PSAT1), an enzyme involved in serine biosynthesis, is overexpressed in non-small cell lung cancer (NSCLC). Elevated PSAT1 appears to enhance the proliferation of NSCLC cells by promoting cell-cycle progression, an effect associated with inhibition of cyclin D1 degradation and altered activity of the Rb-E2F pathway. The results indicate that unrestrained cell-cycle progression in NSCLC is linked to PSAT1 upregulation and constitutive activation of E2F.