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ABSTRACT
Objectives:
Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress.
Methods:
ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo.
Results:
We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models.
Discussion:
our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.
GRAPHICAL ABSTRACT
Acknowledgements
T-T and W-R W conceived the main idea. H-Y M, Y-H, R-B W, M-Y M, X-Y L and Y-Z performed the experiments and analyzed the data. H-YM and Y-Z drafted the manuscript. W-RW and Y-H reviewed drafts of the paper and improved the manuscript. H-YM and R-BW performed the animal experiments and collected the data. T-T and W-RW supervised the study and provided funding. All authors approved the final manuscript. The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Ethics Committee of SYSUCC for studies involving humans. The animal study protocol was approved by the Animal Experimental Ethics Committee of SYSUCC.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Availability of data and materials
Analyses of the expression of MTHFD2 in GC were supported by the TCGA database (http://www.cbioportal.org/publicportal/) and the Oncomine database (https://www.oncomine.org/). The pathway analysis was performed with gene set enrichment analysis (version 4.0.3).