IL-8-induced O-GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell-like properties in colon and lung cancer cells
IL-8-induced O-GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell-like properties in colon and lung cancer cells
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DOI：
10.1038/s41388-018-0533-4
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发表时间：
2019-02-28
期刊：
影响因子：
8
通讯作者：
Tanaka, Nobuyuki
中科院分区：
文献类型：
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作者：
Shimizu, Masahiro;Tanaka, Nobuyuki
白细胞介素 8 (IL-8) 是一种促炎趋化因子，与中性粒细胞趋化性和脱颗粒的诱导有关。 IL-8 在许多肿瘤中过度表达，包括结肠癌和肺癌，最近的研究表明 IL-8 在肿瘤微环境中的肿瘤进展中发挥重要作用。然而，IL-8 在肿瘤进展中发挥作用的分子机制尚不清楚。在这项研究中，我们发现 IL-8 在具有癌症干细胞 (CSC) 样特征的结肠癌细胞和肺癌细胞中过度表达，并且是 CSC 特性（包括肿瘤启动能力）所必需的。这些发现表明 IL-8 在 CSC 的发育中发挥着重要作用。我们还表明，IL-8 刺激结肠癌细胞和肺癌细胞可诱导葡萄糖摄取以及葡萄糖转运蛋白 3 (GLUT3) 和葡萄糖胺果糖 6-磷酸转氨酶 (GFAT) 的表达，GFAT 是葡萄糖流向己糖胺生物合成途径的调节剂，从而增强蛋白质 O-GlcNAc 酰化。我们证明这些事件对于结肠癌细胞和肺癌细胞的生成和维持 CSC 样特征是必需的。此外，O-GlcNAcylation 抑制剂 OSMI1 可减少体内 CSC 数量和肿瘤发展。总之，这些结果表明，IL-8 诱导的 O-GlcNAc 酰化是结肠癌细胞和肺癌细胞 CSC 的生成和维持所必需的，并表明该调节途径可作为 CSC 的候选治疗靶点。
Interleukin-8 (IL-8) is a pro-inflammatory chemokine that is associated with induction of chemotaxis and degranulation of neutrophils. IL-8 is overexpressed in many tumors, including colon and lung cancer, and recent studies demonstrated essential roles for IL-8 in tumor progression within the tumor microenvironment. However, the molecular mechanism underlying the functions of IL-8 in tumor progression is unclear. In this study, we found that IL-8 is overexpressed in colon and lung cancer cells with cancer stem cell (CSC)-like characteristics and is required for CSC properties, including tumor-initiating abilities. These findings suggest that IL-8 plays an essential role in the development of CSCs. We also showed that IL-8 stimulation of colon and lung cancer cells-induced glucose uptake and expressions of glucose transporter 3 (GLUT3) and glucosamine fructose-6-phosphate aminotransferase (GFAT), a regulator of glucose flux to the hexosamine biosynthetic pathway, resulting in enhancement of protein O-GlcNAcylation. We demonstrated that these events are required for the generation and maintenance CSC-like characteristics of colon and lung cancer cells. Moreover, an O-GlcNAcylation inhibitor, OSMI1, reduced CSC number and tumor development in vivo. Together, these results reveal that IL-8-induced O-GlcNAcylation is required for generation and maintenance of CSCs of colon and lung cancer cells and suggests this regulatory pathway as a candidate therapeutic target of CSCs.