Meng Xiangpeng, Peng Fang, Yu Shijie, Chi Xinming, Wang Wenchi, Shao Shujuan
Liaoning Key Laboratory of Proteomics, Dalian Medical University, Dalian, 116044, China.
Department of Pathologic, The Second Hospital of Dalian Medical University, Dalian, 116011, China.
J Cancer Res Clin Oncol. 2024 May 3;150(5):228. doi: 10.1007/s00432-024-05752-z.
Lung cancer is a serious threat to human health and is the first leading cause of cancer death. Ferroptosis, a newly discovered form of programmed cell death associated with redox homeostasis, is of particular interest in the lung cancer, given the high oxygen environment of lung cancer. NADPH has reducing properties and therefore holds the potential to resist ferroptosis. Resistance to ferroptosis exists in lung cancer, but the role of NADK in regulating ferroptosis in lung cancer has not been reported yet.
Immunohistochemistry (IHC) was used to analyse the expression of NADK in 86 cases of lung adenocarcinoma(LUAD) and adjacent tissues, and a IHC score was assigned to each sample. Chi-square and kaplan-meier curve was performed to analyse the differences in metastasis and five-year survival between the two groups with NADK high or low scores. Proliferation of NADK-knockdown LUAD cell lines was detected in vivo and vitro. Furthermore, leves of ROS, MDA and Fe were measured to validate the effect and mechanism of NADK on ferroptosis in LUAD.
The expression of NADK was significantly evaluated in LUAD tissues as compared to adjacent non-cancerous tissues. The proliferation of NADK-knockdown cells was inhibited both in vivo and vitro, and increasing levels of intracellular ROS, Fe and lipid peroxide products (MDA) were observed. Furthermore, NADK-knockdown promoted the ferroptosis of LUAD cells induced by Erastin/RSL3 by regulating the level of NADPH and the expression of FSP1. Knockdown of NADK enhanced the sensitivities of LUAD cells to Erastin/RSL3-induced ferroptosis by regulating NADPH level and FSP1 expression.
NADK is over-expressed in LUAD patients. Knockdown of NADK inhibited the proliferation of LUAD cells both in vitro and in vivo and promotes the Erastin/RSL3-induced ferroptosis of LUAD cells by down-regulating the NADPH/FSP1 axis.
肺癌是对人类健康的严重威胁，是癌症死亡的首要原因。铁死亡是一种新发现的与氧化还原稳态相关的程序性细胞死亡形式，鉴于肺癌的高氧环境，在肺癌中备受关注。NADPH具有还原性，因此具有抵抗铁死亡的潜力。肺癌中存在对铁死亡的抗性，但NADK在调节肺癌铁死亡中的作用尚未见报道。
采用免疫组织化学（IHC）分析86例肺腺癌（LUAD）及癌旁组织中NADK的表达，并对每个样本进行IHC评分。采用卡方检验和Kaplan-Meier曲线分析NADK高评分组和低评分组之间转移和五年生存率的差异。检测NADK敲低的LUAD细胞系在体内外的增殖情况。此外，检测活性氧（ROS）、丙二醛（MDA）和铁的水平，以验证NADK对LUAD铁死亡的影响及机制。
与癌旁非癌组织相比，LUAD组织中NADK的表达显著上调。NADK敲低的细胞在体内外的增殖均受到抑制，且细胞内ROS、铁和脂质过氧化产物（MDA）水平升高。此外，NADK敲低通过调节NADPH水平和FSP1的表达促进了Erastin/RSL-3诱导的LUAD细胞铁死亡。敲低NADK通过调节NADPH水平和FSP1表达增强了LUAD细胞对Erastin/RSL-3诱导的铁死亡的敏感性。
NADK在LUAD患者中过表达。敲低NADK在体外和体内均抑制LUAD细胞的增殖，并通过下调NADPH/FSP1轴促进Erastin/RSL-3诱导的LUAD细胞铁死亡。
