Department of Hepatopancreatobiliary Surgery, the Third Affiliated Hospital of Soochow University, 185 Juqian St, 213003, Changzhou, Jiangsu, China.
J Bioenerg Biomembr. 2022 Dec;54(5-6):283-291. doi: 10.1007/s10863-022-09949-0. Epub 2022 Oct 29.
Pancreatic adenocarcinoma (PAAD) is the third leading cause of cancer-related deaths, with a 5-year relative survival rate of 6%. Hence, novel therapeutic targets need to be urgently explored for PAAD. Recently, oxidative phosphorylation (OXPHOS) has been identified to contribute to the development of PAAD. Nicotinamide adenine dinucleotide + hydrogen (NADH) dehydrogenase (ubiquinone) 1 alpha subcomplex 4 (NDUFA4) is known to affect the mitochondrial respiration pathway. However, the function of NDUFA4 in PAAD remains unclear. In this study, NDUFA4 expression was examined in samples from patients with PAAD using real-time polymerase chain reaction and immunohistochemical staining. Furthermore, cell proliferation and cell cycle were analyzed using Cell Counting Kit-8 assay and flow cytometry. A xenograft tumor model derived from a PAAD cell line was developed to validate the in vitro findings. NDUFA4 was observed to be upregulated in the PAAD samples, and high levels were associated with a poor survival rate. NDUFA4 knockdown reduced cell proliferation by inducing G1 arrest in SW1990 cells. Mechanistically, NDUFA4 knockdown decreased the oxygen consumption rate, cellular adenosine triphosphate level, mitochondrial complex IV activity, and protein levels of COX6C and COX5B, which indicated the suppression of OXPHOS. In contrast, NDUFA4 overexpression exerted the opposite effects. Finally, NDUFA4 knockdown significantly inhibited the growth of the xenograft tumor derived from the SW1990 cell line in vivo. Therefore, NDUFA4 contributes to PAAD proliferation by enhancing OXPHOS.
胰腺导管腺癌（PAAD）是癌症相关死亡的第三大主要原因，其 5 年相对生存率为 6%。因此，迫切需要探索治疗 PAAD 的新靶点。最近，氧化磷酸化（OXPHOS）被认为有助于 PAAD 的发展。烟酰胺腺嘌呤二核苷酸+氢（NADH）脱氢酶（泛醌）1 亚基α 4（NDUFA4）已知会影响线粒体呼吸途径。然而，NDUFA4 在 PAAD 中的功能尚不清楚。在这项研究中，使用实时聚合酶链反应和免疫组织化学染色检查了来自 PAAD 患者的样本中的 NDUFA4 表达。此外，使用细胞计数试剂盒-8 测定法和流式细胞术分析了细胞增殖和细胞周期。开发了源自 PAAD 细胞系的异种移植肿瘤模型来验证体外发现。观察到 NDUFA4 在 PAAD 样本中上调，高水平与生存率降低相关。NDUFA4 敲低通过诱导 SW1990 细胞中的 G1 期停滞来减少细胞增殖。在机制上，NDUFA4 敲低降低了耗氧量、细胞三磷酸腺苷水平、线粒体复合物 IV 活性以及 COX6C 和 COX5B 的蛋白水平，这表明 OXPHOS 受到抑制。相比之下，NDUFA4 过表达则产生相反的效果。最后，NDUFA4 敲低显著抑制了体内源自 SW1990 细胞系的异种移植肿瘤的生长。因此，NDUFA4 通过增强 OXPHOS 促进 PAAD 增殖。
