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. 2023 Sep 20;14(9):617.
doi: 10.1038/s41419-023-06142-y.

Hypoxia-induced ALDH3A1 promotes the proliferation of non-small-cell lung cancer by regulating energy metabolism reprogramming

Yang Chen #  1   2 , Hongfei Yan #  3   4 , Lirong Yan  5 , Ximing Wang  1 , Xiaofang Che  3   4   6 , Kezuo Hou  3   4   6 , Yi Yang  7 , Xuena Li  8 , Yaming Li  8 , Ye Zhang  9 , Xuejun Hu  10
Affiliations

Hypoxia-induced ALDH3A1 promotes the proliferation of non-small-cell lung cancer by regulating energy metabolism reprogramming

Yang Chen et al. Cell Death Dis. .

Abstract

Aldehyde dehydrogenase 3A1 (ALDH3A1) is an NAD+-dependent enzyme that is closely related to tumor development. However, its role in non-small-cell lung cancer (NSCLC) has not been elucidated. This study aimed to clarify the mechanism of ALDH3A1 and identify potential therapeutic targets for NSCLC. Here, for the first time, we found that ALDH3A1 expression could be induced by a hypoxic environment in NSCLC. ALDH3A1 was highly expressed in NSCLC tissue, especially in some late-stage patients, and was associated with a poor prognosis. In mechanistic terms, ALDH3A1 enhances glycolysis and suppresses oxidative phosphorylation (OXPHOS) to promote cell proliferation by activating the HIF-1α/LDHA pathway in NSCLC. In addition, the results showed that ALDH3A1 was a target of β-elemene. ALDH3A1 can be downregulated by β-elemene to inhibit glycolysis and enhance OXPHOS, thus suppressing NSCLC proliferation in vitro and in vivo. In conclusion, hypoxia-induced ALDH3A1 is related to the energy metabolic status of tumors and the efficacy of β-elemene, providing a new theoretical basis for better clinical applications in NSCLC.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. ALDH3A1 expression characteristics in NSCLC.
A GSE18842 showed that ALDH3A1 was upregulated in NSCLC. B The expression of ALDH3A1 in normal and tumor tissues. C The Kaplan–Meier plot indicated that ALDH3A1 was associated with a poor prognosis of NSCLC. D Expression of ALDH3A1 in patients with different pathological stages. E GSE30979 showed that ALDH3A1 was upregulated in hypoxic patients with NSCLC. F ALDH3A1 and hypoxia-inducible factor-1α (HIF-1α) were significantly increased with hypoxia at 0, 12, 24, and 48. G GSEA enrichment analysis of ALDH3A1 in NSCLC with the TCGA dataset. H Immunofluorescence staining and correlation analysis of tissue samples. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 2
Fig. 2. ALDH3A1 promotes cell proliferation and regulates the reprogramming of energy metabolism in NSCLC.
A MTT assay showed the effects of ALDH3A1 on the proliferation of NSCLC. B Clone formation assay indicated the effects of ALDH3A1 on the proliferation of NSCLC. C EDU assay indicated the effects of ALDH3A1 on the proliferation of NSCLC. D Effect of ALDH3A1 on the cell cycle distribution of A549 and H1299 cells. Data are presented as mean ± SD (n = 3). Student’s t-tests were used for statistical analyses. E The respective effects of ALDH3A1 on the metabolites in glycolysis. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 3
Fig. 3. ALDH3A1 promotes cell proliferation via enhancing glycolysis in NSCLC.
A Lactate production in A549 and H1299 cells in the presence of 2-DG. B CCK-8 showed the effects of 2-DG on the proliferation of A549 and H1299 cells. C Clone formation assay indicated the effects of 2-DG on the proliferation of A549 and H1299 cells. D EDU assay indicated the effects of 2-DG on the proliferation of A549 and H1299 cells. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 4
Fig. 4. ALDH3A1 is a potential target of β-elemene.
A Molecular docking of ALDH3A1 and β-elemene. B, C The expression of ALDH3A1 on the mRNA and protein levels after treatment with β-elemene. D The clones were enumerated when NSCLC cells were treated with sh-ALDH3A1 and β-elemene. E EdU assay was conducted using two cell lines with sh-ALDH3A1 and β-elemene treatment. F NSCLC cells transduced with sh-NC and sh-ALDH3A1 with or without β-elemene were subjected to Western blotting to identify the cell cycle proteins. G The respective effects of β-elemene, sh-ALDH3A1, and their combination on the metabolites in glycolysis. *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 5
Fig. 5. ALDH3A1 reprograms energy metabolism via the HIF-1α/LDHA pathway.
A Western blotting was used to detect the protein expression associated with the HIF-1α/LDHA pathway of NSCLC cells transduced with Sh-NC and Sh-ALDH3A1, as well as OE-NC and OE-ALDH3A1, with and without treatment with Octyl-α-KG (1 mM). B Combinatorial treatment effects of β-elemene and Sh-ALDH3A1 on glycolysis genes on the mRNA level. C Western blotting was used to detect protein expression associated with the HIF-1α/LDHA pathway of NSCLC cells transduced with sh-NC and sh-ALDH3A1 with and without treatment with β-elemene (25 μg/ml). *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 6
Fig. 6. Experimental validation in vivo.
A The flow diagram of the construction of the mice model to identify the efficacy of ALDH3A1. B The 18FDG micro-PET scan was used for the mice model treated with β-elemene and/or sh-ALDH3A1. C The SUV values of the tumors in vivo. D Photographs of tumors after the injection of Sh-NC (left) and Sh-ALDH3A1 (right) with and without β-elemene treatment. E The weight and volume of the tumors. F Xenograft tumor tissues treated for 15 days, as indicated, were evaluated via hematoxylin and eosin staining and immunohistochemistry (×200). *P < 0.05, **P < 0.01, ***P < 0.001.
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