Liu Yuanda, Li Changfeng, Cui Xilun, Liu Chang, Xiao Pengtuo, Yang Wei
Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China.
Department of Endoscopy Center, China-Japan Union Hospital of Jilin University, Changchun, China.
Cell Signal. 2025 Mar;127:111565. doi: 10.1016/j.cellsig.2024.111565. Epub 2024 Dec 14.
Gastric cancer (GC) is among the most malignant tumors, with the lowest five-year survival rate, and limited treatment options. Kynureninase (KYNU), is a key molecule in tryptophan metabolism and promotes tumor progression and immunosuppression. Cuproptosis is a non-apoptotic cell death mechanism, primarily due to oxidative stress caused by copper ion accumulation, that is related to tumor progression and drug resistance. KYNU can inhibit ferroptosis of tumor cells by alleviating oxidative stress. Here, we explored whether KYNU can regulate the biological behavior of GC and cuproptosis.
Expression, prognostic association, and functional analysis of KYNU in GC and tumor-adjacent tissues were analyzed using data from The Cancer Genome Atlas and clinical specimens. Effects of KYNU on proliferation, invasion, metastasis, and cuproptosis of GC cells were detected by CCK8, clone formation, Transwell, and flow cytometry assays. Elesclomol (ES) combined with CuCl were used to induce cuproptosis in GC cells. 3-hydroxyanthranilic acid (3-HA) was used to indicate KYNU function. Key cuproptosis genes were detected by qPCR and WB. The effects of KYNU on GC cell behavior and cuproptosis through lipoic acid synthetase (LIAS) were verified by stable overexpression and knockdown of LIAS.
KYNU is highly expressed in GC, and high KYNU expression is an independent predictor of poor prognosis in patients with GC. KYNU can promote GC cell proliferation, invasion, metastasis, and cuproptosis resistance. 3-HA had a certain inhibitory effect on the expression of LIAS, but it was not significant. KYNU had no effect on the intracellular 3-HA level. KYNU expression was negatively correlated with that of LIAS, and promoted GC cell proliferation, invasion, metastasis, and cuproptosis resistance by downregulating LIAS.
KYNU can promote GC proliferation, invasion, metastasis, and cuproptosis resistance.This effect is not associated with its metabolite 3-HA, but is achieved by a non classical mechanisms that downregulating the expression of LIAS, a key gene of cuproptosis.
胃癌（GC）是最恶性的肿瘤之一，五年生存率最低，治疗选择有限。犬尿氨酸酶（KYNU）是色氨酸代谢的关键分子，可促进肿瘤进展和免疫抑制。铜死亡是一种非凋亡性细胞死亡机制，主要由于铜离子积累引起的氧化应激，与肿瘤进展和耐药性有关。KYNU可通过减轻氧化应激来抑制肿瘤细胞的铁死亡。在此，我们探讨了KYNU是否能调节GC的生物学行为和铜死亡。
使用来自癌症基因组图谱的数据和临床标本分析KYNU在GC和癌旁组织中的表达、预后相关性及功能。通过CCK8、克隆形成、Transwell和流式细胞术检测KYNU对GC细胞增殖、侵袭、转移和铜死亡的影响。使用艾力可（ES）联合氯化铜诱导GC细胞发生铜死亡。用3-羟基邻氨基苯甲酸（3-HA）来指示KYNU的功能。通过qPCR和WB检测关键铜死亡基因。通过稳定过表达和敲低LIAS来验证KYNU通过硫辛酸合成酶（LIAS）对GC细胞行为和铜死亡的影响。
KYNU在GC中高表达，高KYNU表达是GC患者预后不良的独立预测因子。KYNU可促进GC细胞增殖、侵袭、转移和铜死亡抗性。3-HA对LIAS的表达有一定抑制作用，但不显著。KYNU对细胞内3-HA水平无影响。KYNU表达与LIAS表达呈负相关，并通过下调LIAS促进GC细胞增殖、侵袭、转移和铜死亡抗性。
KYNU可促进GC增殖、侵袭、转移和铜死亡抗性。这种作用与其代谢产物3-HA无关，而是通过下调铜死亡关键基因LIAS的表达这一非经典机制实现的。
