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.
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Data Availability
The datasets generated during this study are available from the corresponding author on reasonable request.
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This work was supported by the Applied Basic Research of Changzhou Technology Bureau (CJ20200095).
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Xuemin Chen, Xinquan Wu, and Yue Zhang contributed to the conception and design of the study. Material preparation and data collection and analysis were performed by Yue Zhang, Mengchen Ge, Yuxiang Chen, Yan Yang, Weibo Chen, Di Wu, and Huihua Cai. The first draft of the manuscript was written by Yue Zhang, and all authors commented on previous versions of the manuscript. All authors read and approved the final version of the manuscript to be submitted.
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Animal experiments were performed according to the institutional animal welfare guidelines and were approved by the Animal Care Committee of the Third Affiliated Hospital of Soochow University.
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Yue Zhang and Mengchen Ge are the co-first author, they contribute equally to this work.
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Zhang, Y., Ge, M., Chen, Y. et al. NDUFA4 promotes cell proliferation by enhancing oxidative phosphorylation in pancreatic adenocarcinoma. J Bioenerg Biomembr 54, 283–291 (2022). https://doi.org/10.1007/s10863-022-09949-0
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DOI: https://doi.org/10.1007/s10863-022-09949-0