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Drug-induced lactate confers ferroptosis resistance via p38-SGK1-NEDD4L-dependent upregulation of GPX4 in NSCLC cells.

ABSTRACT: Ferroptosis is a newly defined non-apoptotic programmed cell death resulting from the accumulation of lipid peroxides. Whether ferroptosis plays any role in chemotherapy remains to be established. Here, we reported that ferroptosis represents a part of the chemotherapeutic drug etoposide-induced cell death response in Small Cell Lung Cancer (SCLC) cells and adaptive signaling molecule lactate protects Non-Small Cell Lung Cancer (NSCLC) from etoposide-induced ferroptosis. Lactate derived from metabolic reprogramming increases the expression of glutathione peroxidase 4 (GPX4) to promote ferroptosis resistance in NSCLC. Furthermore, we identified E3-ubiquitin ligase NEDD4L as a major regulator of GPX4 stability. Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4. Our data implicated the role of ferroptosis in chemotherapeutic resistance and identified a novel post-translational regulatory mechanism for the key Ferroptosis mediator GPX4.

SUBMITTER: Cheng F

PROVIDER: S-EPMC10185500 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Drug-induced lactate confers ferroptosis resistance via p38-SGK1-NEDD4L-dependent upregulation of GPX4 in NSCLC cells.

Cheng Feng F Dou Jintao J Yang Yi Y Sun Shaojie S Chen Ruiqi R Zhang Zhijian Z Wei Huijun H Li Jianhui J Wu Zhihao Z

Cell death discovery 20230515 1

Ferroptosis is a newly defined non-apoptotic programmed cell death resulting from the accumulation of lipid peroxides. Whether ferroptosis plays any role in chemotherapy remains to be established. Here, we reported that ferroptosis represents a part of the chemotherapeutic drug etoposide-induced cell death response in Small Cell Lung Cancer (SCLC) cells and adaptive signaling molecule lactate protects Non-Small Cell Lung Cancer (NSCLC) from etoposide-induced ferroptosis. Lactate derived from met ...[more]

PMID: 37188685

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Project description:BackgroundRecent studies have reported that the circadian transcription factor aryl hydrocarbon receptor nuclear translocator like 2 (ARNTL2) promotes the metastatic progression of lung adenocarcinoma. However, the molecular mechanisms of ARNTL2 in non-small cell lung cancer (NSCLC) cell growth and proliferation remain to be explored.MethodsThe expression of ARNTL2 and acyl-CoA thioesterase 7 (ACOT7) in lung cancer patients was analyzed based on TCGA database. Gain-of-function of ARNTL2 and ACOT7 was conducted by transfecting the cells with plasmids or lentivirus. Knockdown assay was carried out by siRNAs. Western blot and qRT-PCR were performed to check the protein and mRNA expression. Dual luciferase and ChIP-qPCR assay was applied to check the interaction of ARNTL2 on ACOT7's promoter sequence. Triglyceride level, MDA production, the activity of casapase 3 to caspase 7, and lipid ROS were measured by indicated assay kit. Cellular function was detected by CCK8, colony formation and flow cytometry analysis of cell death and cell cycle.ResultsWe demonstrated that ARNTL2 upregulation of ACOT7 was critical for NSCLC cell growth and proliferation. Firstly, overexpression of ARNTL2 conferred the poor prognosis of LUAD patients and supported the proliferation of NSCLC cells. Based on molecular experiments, we showed that ARNTL2 potentiated the transcription activity of ACOT7 gene via direct binding to ACOT7's promoter sequence. ACOT7 high expression was correlated with the worse prognosis of LUAD patients. Gain-of-function and loss-of-function experiments revealed that AOCT7 contributed to NSCLC cell growth and proliferation. ACOT7 regulated the apoptosis and ferroptosis of NSCLC cells, while exhibited no effect on cell cycle progression. ACOT7 overexpression also potentiated fatty acid synthesis and suppressed lipid peroxidation. Lastly, we showed that ARNTL2 knockdown and overexpression inhibited and promoted the cellular triglyceride production and subsequent cell proliferation, which could be reversed by ACOT7 overexpression and knockdown.ConclusionOur study illustrated the oncogenic function of ARNTL2/ACOT7 axis in the development of NSCLC. Targeting ARNTL2 or ACOT7 might be promising therapeutic strategies for NSCLC patients with highly expressed ARNTL2.

Dataset Information

Drug-induced lactate confers ferroptosis resistance via p38-SGK1-NEDD4L-dependent upregulation of GPX4 in NSCLC cells.

Publications

Drug-induced lactate confers ferroptosis resistance via p38-SGK1-NEDD4L-dependent upregulation of GPX4 in NSCLC cells.

Similar Datasets

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