Lung cancer (LC) is one of the major malignant diseases threatening human health. The study aimed to identify the effect of citrulline on the malignant phenotype of LC cells and to further disclose the potential molecular mechanism of citrulline in regulating the development of LC, providing a novel molecular biological basis for the clinical treatment of LC. The effects of citrulline on the viability, proliferation, migration, and invasion of LC cells (A549, H1299) were validated by CCK‐8, colony formation, EdU, and transwell assays. The cell glycolysis was assessed via determining the glucose uptake, lactate production, ATP levels, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR). RNA‐seq and molecular docking were performed to screen for citrulline‐binding target proteins. Western blotting experiments were conducted to examine the expression of related signaling pathway molecules. In addition, the impacts of citrulline on LC growth in vivo were investigated by constructing mouse models. Citrulline augmented the viability of LC cells in a concentration and time‐dependent manner. The proliferation, migration, invasion, glycolysis, and EMT processes of LC cells were substantially enhanced after citrulline treatment. Bioinformatics analysis indicated that citrulline could bind to RAB3C protein. Western blotting results indicated that citrulline activated the IL‐6/STAT3 pathway by binding to RAB3C. In addition, animal experiments disclosed that citrulline promoted tumor growth in mice. Citrulline accelerated the glycolysis and activated the IL6/STAT3 pathway through the RAB3C protein, consequently facilitating the development of LC.

中文翻译：

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瓜氨酸通过调节RAB3C促进肺癌细胞的糖酵解、增殖和转移


肺癌（LC）是威胁人类健康的主要恶性疾病之一。该研究旨在明确瓜氨酸对LC细胞恶性表型的影响，进一步揭示瓜氨酸调节LC发生发展的潜在分子机制，为LC的临床治疗提供新的分子生物学基础。通过 CCK-8、集落形成、EdU 和 Transwell 测定验证了瓜氨酸对 LC 细胞（A549、H1299）的活力、增殖、迁移和侵袭的影响。通过测定葡萄糖摄取、乳酸产生、ATP 水平、细胞外酸化率 (ECAR) 和耗氧率 (OCR) 来评估细胞糖酵解。进行 RNA 测序和分子对接来筛选瓜氨酸结合靶蛋白。进行Western blotting实验来检查相关信号通路分子的表达。此外，通过构建小鼠模型研究了瓜氨酸对LC体内生长的影响。瓜氨酸以浓度和时间依赖性方式增强LC细胞的活力。瓜氨酸处理后LC细胞的增殖、迁移、侵袭、糖酵解和EMT过程显着增强。生物信息学分析表明瓜氨酸可以与RAB3C蛋白结合。 Western blotting 结果表明瓜氨酸通过与 RAB3C 结合激活 IL-6/STAT3 通路。此外，动物实验表明瓜氨酸可促进小鼠肿瘤生长。瓜氨酸通过 RAB3C 蛋白加速糖酵解并激活 IL6/STAT3 通路，从而促进 LC 的发生。