Dataset Information

Arsenic exposure increases susceptibility to Ptpn11-induced malignancy in mouse embryonic fibroblasts through mitochondrial hypermetabolism.

ABSTRACT:

Objective

To explore the synergistic effect and metabolic mechanism of chronic arsenic exposure and PTPN11 gain-of-function mutation on tumorigenesis.

Methods

Arsenic-transformed Ptpn11^+/+ (WT-As) and Ptpn11^D61G/+ -mutant (D61G-As) mouse embryonic fibroblasts (MEFs) were established by chronic treatment of low-dose arsenic. We used cell counting, plate colony and soft agar colony formation, and a nude mouse xenograft model to detect malignant transformation and tumorigenesis in vitro and in vivo. To detect mitochondrial oxidative phosphorylation (OXPHOS), we used Seahorse real-time cell metabolic analysis as well as adenosine triphosphate (ATP) and ROS production assays. Lastly, we examined mTOR signaling pathway changes by western blotting.

Results

Low-dose arsenic exposure promoted WT MEFs proliferation and exacerbated malignancy driven by Ptpn11^D61G/+ mutation. Additionally, Ptpn11^D61G/+ -mutant MEFs exhibited increased mitochondrial metabolism and low-dose arsenic amplified this malignant metabolic activity. Mechanistically, the mTOR signaling pathway was activated in Ptpn11^D61G/+ -mutant MEFs and was further phosphorylated in arsenic-treated MEFs expressing Ptpn11^D61G/+ . Critically, tumorigenesis induced by the synergistic effect of low-dose arsenic and Ptpn11^D61G/+ mutation was prevented by mTOR pathway inhibition via rapamycin.

Conclusion

This study found that metabolic reprogramming, particularly mitochondrial hyperactivation, is a core mechanism underlying tumorigenesis induced by the synergistic effect of Ptpn11^D61G/+ mutation and arsenic exposure. Furthermore, these findings suggested mTOR is a therapeutic target for Ptpn11-associated cancers.

SUBMITTER: Yang F

PROVIDER: S-EPMC9360862 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Arsenic exposure increases susceptibility to <i>Ptpn11</i>-induced malignancy in mouse embryonic fibroblasts through mitochondrial hypermetabolism.

Yang Fan F Tan Zhenya Z Dai Yuanjuan Y Wang Xingxing X Huang Zhen Z Kan Chen C Wang Siying S

American journal of translational research 20220715 7

<h4>Objective</h4>To explore the synergistic effect and metabolic mechanism of chronic arsenic exposure and <i>PTPN11</i> gain-of-function mutation on tumorigenesis.<h4>Methods</h4>Arsenic-transformed <i>Ptpn11<sup>+/+</sup></i> (WT-As) and <i>Ptpn11<sup>D61G/+</sup></i> -mutant (D61G-As) mouse embryonic fibroblasts (MEFs) were established by chronic treatment of low-dose arsenic. We used cell counting, plate colony and soft agar colony formation, and a nude mouse xenograft model to detect malig ...[more]

PMID: 35958497

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