Lactate enhances NMNAT1 lactylation to sustain nuclear NAD+ salvage pathway and promote survival of pancreatic adenocarcinoma cells under glucose-deprived conditions

The aim of this study was to investigate the underlying molecular mechanism behind the promotion of cell survival under conditions of glucose deprivation by l-lactate. To accomplish this, we performed tissue microarray and immunohistochemistry staining to analyze the correlation between the abundanc...

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Veröffentlicht in:Cancer letters 2024-04, Vol.588, p.216806-216806, Article 216806
Hauptverfasser: Huang, Huimin, Wang, Shitong, Xia, Hongping, Zhao, Xingling, Chen, Kaiyuan, Jin, Guihua, Zhou, Shipeng, Lu, Zhaoliang, Chen, Tongke, Yu, Huajun, Zheng, Xiaoqun, Huang, Haishan, Lan, Linhua
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Sprache:eng
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Zusammenfassung:The aim of this study was to investigate the underlying molecular mechanism behind the promotion of cell survival under conditions of glucose deprivation by l-lactate. To accomplish this, we performed tissue microarray and immunohistochemistry staining to analyze the correlation between the abundance of pan-Lysine lactylation and prognosis. In vivo evaluations of tumor growth were conducted using the KPC and nude mice xenograft tumor model. For mechanistic studies, multi-omics analysis, RNA interference, and site-directed mutagenesis techniques were utilized. Our findings robustly confirmed that l-lactate promotes cell survival under glucose deprivation conditions, primarily by relying on GLS1-mediated glutaminolysis to support mitochondrial respiration. Mechanistically, we discovered that l-lactate enhances the NMNAT1-mediated NAD+ salvage pathway while concurrently inactivating p-38 MAPK signaling and suppressing DDIT3 transcription. Notably, Pan-Kla abundance was significantly upregulated in patients with Pancreatic adenocarcinoma (PAAD) and associated with poor prognosis. We identified the 128th Lysine residue of NMNAT1 as a critical site for lactylation and revealed EP300 as a key lactyltransferase responsible for catalyzing lactylation. Importantly, we elucidated that lactylation of NMNAT1 enhances its nuclear localization and maintains enzymatic activity, thereby supporting the nuclear NAD+ salvage pathway and facilitating cancer growth. Finally, we demonstrated that the NMNAT1-dependent NAD+ salvage pathway promotes cell survival under glucose deprivation conditions and is reliant on the activity of Sirt1. Collectively, our study has unraveled a novel molecular mechanism by which l-lactate promotes cell survival under glucose deprivation conditions, presenting a promising strategy for targeting lactate and NAD+ metabolism in the treatment of PAAD. •Lactate relies on GLS1-mediated glutaminolysis to promote PAAD cell survival during glucose deprivation.•Lactate prevents NAD+ depletion during glucose deprivation by preserving the NMNAT1-mediated NAD+ salvage pathway.•Lactylation at the 128th Lysine residue promotes the nuclear translocation and maintains the enzymatic activity of NMNAT1.•Lactate sustains the NMNAT1-mediated NAD+ pathway to activate Sirt1-dependent cell survival during glucose deprivation.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2024.216806