印迹基因和衰老基因：色氨酸饥饿条件下癌细胞存活的潜在介质。
Imprinted and ancient gene: a potential mediator of cancer cell survival during tryptophan deprivation.
机构信息
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
出版信息
Cell Commun Signal. 2018 Nov 22;16(1):88. doi: 10.1186/s12964-018-0301-7.
BACKGROUND
Depletion of tryptophan and the accumulation of tryptophan metabolites mediated by the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1), trigger immune cells to undergo apoptosis. However, cancer cells in the same microenvironment appear not to be affected. Mechanisms whereby cancer cells resist accelerated tryptophan degradation are not completely understood. We hypothesize that cancer cells co-opt IMPACT (the product of IMPrinted and AnCienT gene), to withstand periods of tryptophan deficiency.
METHODS
A range of bioinformatic techniques including correlation and gene set variation analyses was applied to genomic datasets of cancer (The Cancer Genome Atlas) and normal (Genotype Tissue Expression Project) tissues to investigate IMPACT's role in cancer. Survival of IMPACT-overexpressing GL261 glioma cells and their wild type counterparts cultured in low tryptophan media was assessed using fluorescence microscopy and MTT bio-reduction assay. Expression of the Integrated Stress Response proteins was measured using Western blotting.
RESULTS
We found IMPACT to be upregulated and frequently amplified in a broad range of clinical cancers relative to their non-malignant tissue counterparts. In a subset of clinical cancers, high IMPACT expression associated with decreased activity of pathways and genes involved in stress response and with increased activity of translational regulation such as the mTOR pathway. Experimental studies using the GL261 glioma line showed that cells engineered to overexpress IMPACT, gained a survival advantage over wild-type lines when cultured under limiting tryptophan concentrations. No significant difference in the expression of proteins in the Integrated Stress Response pathway was detected in tryptophan-deprived GL261 IMPACT-overexpressors compared to that in wild-type cells. IMPACT-overexpressing GL261 cells but not their wild-type counterparts, showed marked enlargement of their nuclei and cytoplasmic area when stressed by tryptophan deprivation.
CONCLUSIONS
The bioinformatics data together with our laboratory studies, support the hypothesis that IMPACT mediates a protective mechanism allowing cancer cells to overcome microenvironmental stresses such as tryptophan deficiency.
背景
免疫抑制酶吲哚胺 2,3-双加氧酶 1（IDO1）介导的色氨酸耗竭和色氨酸代谢物的积累，会触发免疫细胞凋亡。然而，同一微环境中的癌细胞似乎不受影响。癌细胞抵抗加速色氨酸降解的机制尚不完全清楚。我们假设癌细胞会利用 IMPACT（印记和古老基因的产物）来抵抗色氨酸缺乏期。
方法
我们应用了一系列生物信息学技术，包括相关性和基因集变异分析，来研究癌症（癌症基因组图谱）和正常组织（基因型组织表达项目）的基因组数据集，以研究 IMPACT 在癌症中的作用。使用荧光显微镜和 MTT 生物还原测定法评估在低色氨酸培养基中培养的 IMPACT 过表达 GL261 神经胶质瘤细胞及其野生型对照的存活情况。使用 Western blot 测量整合应激反应蛋白的表达。
结果
我们发现，相对于其非恶性组织对照物，IMPACT 在广泛的临床癌症中上调且频繁扩增。在一部分临床癌症中，高 IMPACT 表达与应激反应相关途径和基因活性降低以及翻译调节（如 mTOR 途径）活性增加相关。使用 GL261 神经胶质瘤系进行的实验研究表明，在低色氨酸浓度下培养时，过表达 IMPACT 的细胞比野生型系获得了生存优势。在缺乏色氨酸的 GL261 IMPACT 过表达细胞中，未检测到整合应激反应途径中蛋白的表达有显著差异与野生型细胞相比。与野生型细胞相比，在受到色氨酸剥夺应激时，IMPACT 过表达的 GL261 细胞但不是其野生型细胞，其细胞核和细胞质区域明显增大。
结论
生物信息学数据以及我们的实验室研究支持了这样的假设，即 IMPACT 介导了一种保护机制，使癌细胞能够克服微环境应激，如色氨酸缺乏。
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