NDUFA4 promotes cell proliferation by enhancing oxidative phosphorylation in pancreatic adenocarcinoma.

Abstract

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.