Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Cancer Sci. 2024 Nov;115(11):3587-3595. doi: 10.1111/cas.16314. Epub 2024 Aug 28.
Cancer cells show a dynamic metabolic landscape, requiring a sufficient supply of nucleotides to proliferate. They are highly dependent on de novo purine biosynthetic pathways for their nucleotide requirements. Phosphoribosyl pyrophosphate amidotransferase (PPAT), catalyzing the first step of de novo purine biosynthesis, is highly expressed in various cancers. We observed an increased expression of PPAT in nasopharyngeal carcinoma (NPC). Moreover, our ribonucleic acid sequencing analysis showed high PPAT expression in Epstein-Barr virus-positive NPC, which was supported by in vitro analysis. Through a gene knockdown study, we showed that the suppression of PPAT expression reduced the proliferation and invasion of NPC cells. We also demonstrated the regulation of PPAT by glutamine, a cosubstrate for PPAT. A glutamine antagonist, 6-diazo-5-oxo-L-norleucine, blocked glutamine-mediated induction of PPAT and reduced NPC cell proliferation. Immunohistochemical analysis of PPAT in NPC tissues revealed increased expression of PPAT with disease progression, which was significantly associated with poor prognosis. In summary, this study highlighted the biological function of PPAT in NPC, establishing its potential as a novel prognostic biomarker for aggressive NPC and a promising therapeutic target.
癌细胞表现出动态的代谢特征，需要充足的核苷酸供应来增殖。它们高度依赖从头合成途径来满足核苷酸需求。磷酸核糖焦磷酸酰胺转移酶（PPAT）催化从头合成嘌呤途径的第一步，在各种癌症中高度表达。我们观察到鼻咽癌（NPC）中 PPAT 的表达增加。此外，我们的 RNA 测序分析显示 EBV 阳性 NPC 中 PPAT 表达较高，体外分析也支持这一点。通过基因敲低研究，我们表明抑制 PPAT 表达可减少 NPC 细胞的增殖和侵袭。我们还证明了 PPAT 受谷氨酰胺的调节，谷氨酰胺是 PPAT 的共底物。谷氨酰胺拮抗剂 6-二氮-5-氧-L-正亮氨酸阻断了谷氨酰胺介导的 PPAT 诱导，并减少了 NPC 细胞的增殖。NPC 组织中 PPAT 的免疫组织化学分析显示，随着疾病的进展，PPAT 的表达增加，与预后不良显著相关。总之，本研究强调了 PPAT 在 NPC 中的生物学功能，确立了其作为侵袭性 NPC 新型预后生物标志物和有前途的治疗靶点的潜力。
