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The stimulatory effects of asbestos on NADPH-dependent lipid peroxidation in rat liver microsomes.

ABSTRACT: Lipid peroxidation in rat liver microsomes induced by asbestos fibres, crocidolite and chrysotile, is greatly increased in the presence of NADPH, leading to malondialdehyde levels comparable with those induced by CCl4, a very strong inducer of lipid peroxidation. This synergic effect only occurs during the first minutes and could be explained by an increase or a regeneration of the ferrous active sites of asbestos by NADPH, which in turn could rapidly be prevented by the adsorption of microsomal proteins on the surface of the fibres. It is not inhibited by superoxide dismutase, catalase and mannitol, indicating that oxygen radicals are not involved in the reaction. It is also not inhibited by desferrioxamine, indicating that it is not due to a release of free iron ions in solution from the fibres. Lipid peroxidation in NADPH-supplemented microsomes is also greatly increased upon addition of magnetite. This could be linked to the presence of ferrous ions in this solid iron oxide, since the ferric oxides haematite and goethite are completely inactive.

SUBMITTER: Fontecave M

PROVIDER: S-EPMC1147597 | biostudies-other | 1987 Jan

REPOSITORIES: biostudies-other

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Project description:BackgroundOxidative stress is a highly active metabolic process in the liver, that poses great threats to disseminated tumor cells during their colonization. Here, we aimed to investigate how colorectal cancer (CRC) cells overcome lipid peroxidation to sustain their metastatic colonization in the liver.MethodsOrthotopic colorectal liver metastasis (CRLM) and CRC liver colonization mouse models were constructed to determine the roles of lipid peroxidation and AADAC in CRC liver colonization. The levels of lipid peroxidation were detected in cells or tissues. AADAC overexpression in LMs and its clinical relevance were analyzed. The oncogenic role of AADAC in CRC liver colonization was evaluated in cell experiments.ResultsCompared with primary tumors (PTs), liver metastases (LMs) showed significantly lower glutathione to oxidized glutathione (GSH/GSSG) ratio and higher malondialdehyde (MDA) levels in CRLM patients and orthotopic mouse models. Inhibition of lipid peroxidation by liproxstatin-1 promoted CRC liver colonization in mouse models. RNA-seq results revealed AADAC as the most significantly upregulated lipid metabolism related gene in LMs compared with PTs. Analyses of datasets and patient and mouse model samples confirmed that AADAC was upregulated in LMs compared with PTs, and was correlated with poor prognosis. AADAC promoted cell proliferation, and facilitated liver colonization in a mouse model by reducing ROS accumulation, which led to lipid peroxidation and ferroptosis. Mechanistically, AADAC upregulated SLC7A11 by activating NRF2 to inhibit lipid peroxidation, thereby protecting metastatic cells from ferroptosis.ConclusionsAADAC protects metastatic CRC cells from ferroptosis by inhibiting lipid peroxidation in an SLC7A11-dependent manner, thus effectively promoting their metastatic colonization and growth in the liver. Together, our findings suggest that AADAC can act as a prognostic indicator and potential therapeutic target for CRLM.

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The stimulatory effects of asbestos on NADPH-dependent lipid peroxidation in rat liver microsomes.

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