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Gastric cancer depends on aldehyde dehydrogenase 3A1 for fatty acid oxidation.

ABSTRACT: The major source of ATP in cancer cells remains unclear. Here, we examined energy metabolism in gastric cancer cells and found increased fatty acid oxidation and increased expression of ALDH3A1. Metabolic analysis showed that lipid peroxidation by reactive oxygen species led to spontaneous production of 4-hydroxynonenal, which was converted to fatty acids with NADH production by ALDH3A1, resulting in further fatty acid oxidation. Inhibition of ALDH3A1 by knock down using siRNA of ALDH3A1 resulted in significantly reduced ATP production by cancer cells, leading to apoptosis. Oxidative phosphorylation by mitochondria in gastric cancer cells was driven by NADH supplied via fatty acid oxidation. Therefore, blockade of ALDH3A1 together with mitochondrial complex I using gossypol and phenformin led to significant therapeutic effects in a preclinical gastric cancer model.

SUBMITTER: Lee JS

PROVIDER: S-EPMC6841934 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Aldehyde dehydrogenase 3A1 associates with prostate tumorigenesis.

Project description:BackgroundAccumulating evidence demonstrates high levels of aldehyde dehydrogense (ALDH) activity in human cancer types, in part, because of its association with cancer stem cells. Whereas ALDH1A1 and ALDH7A1 isoforms were reported to associate with prostate tumorigenesis, whether other ALDH isoforms are associated with prostate cancer (PC) remains unclear.MethodsALDH3A1 expression was analysed in various PC cell lines. Xenograft tumours and 54 primary and metastatic PC tumours were stained using immunohistochemistry for ALDH3A1 expression.ResultsIn comparison with the non-stem counterparts, a robust upregulation of ALDH3A1 was observed in DU145-derived PC stem cells (PCSCs). As DU145 PCSCs produced xenograft tumours with more advanced features compared with those derived from DU145 cells, higher levels of ALDH3A1 were detected in the former; a dramatic elevation of ALDH3A1 occurred in DU145 cell-derived lung metastasis compared with local xenograft tumours. Furthermore, while ALDH3A1 was not observed in prostate glands, ALDH3A1 was clearly present in PIN, and further increased in carcinomas. In comparison with the paired local carcinomas, ALDH3A1 was upregulated in lymph node metastatic tumours; the presence of ALDH3A1 in bone metastatic PC was also demonstrated.ConclusionsWe report here the association of ALDH3A1 with PC progression.

| S-EPMC4021532 | biostudies-literature

Nrf2 depletion sensitizes pancreatic cancer cells to gemcitabine via aldehyde dehydrogenase 3a1 repression.

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Monitoring of fatty aldehyde dehydrogenase by formation of pyrenedecanoic acid from pyrenedecanal.

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Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes.

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Development of selective inhibitors for human aldehyde dehydrogenase 3A1 (ALDH3A1) for the enhancement of cyclophosphamide cytotoxicity.

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Project description:Our previous studies have confirmed that transforming growth factor-β (TGF-β) plays an important role in tumor metastasis, and the serum deprivation protein response (SDPR) is a potential downstream target of TGF-β. However, the role and mechanism of SDPR in gastric cancer are still unclear. We performed gene microarray, bioinformation analysis, combined with in vivo and in vitro experimental verification, we identified that SDPR is significantly downregulated in gastric cancer, and participates in TGF-β-mediated tumour metastasis. Mechanically, SDPR interacts with extracellular signal-regulated kinase (ERK) and inhibits fatty acid metabolism key gene Carnitine palmitoyl transferase 1A (CPT1A) at transcriptional level by supressing ERK/PPAR pathway. Our findings suggest that the TGF-β/SDPR/CPT1A axis play an important role in the fatty acid oxidation of gastric cancer, and provides a new insight into the crosstalk of tumour microenvironments and metabolism reprogramming and suggest that strategies to intervene the fatty acid metabolism may therapy gastric cancer metastasis.

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Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo.

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Project description: Not available

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Obesity and fatty acid oxidation

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