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Αλέξανδρος Γ. Σφακιανάκης

Wednesday, May 19, 2021

MTHFD2 facilitates breast cancer cell proliferation via the AKT signaling pathway

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Exp Ther Med. 2021 Jul;22(1):703. doi: 10.3892/etm.2021.10135. Epub 2021 May 2.

ABSTRACT

MTHFD2 is a folate-coupled mitochondrial metabolic enzyme which has been extensively studied in breast cancer; however, its molecular functions in this cancer remain unclear. The current study aimed to reveal the underlying mechanism of breast cancer. MTHFD2 expression status and prognostic value were determined using the Gene Expression Profiling Interactive Analysis database. To determine the function of MTHFD2 in breast cancer, MCF-7 cells with stable overexpression of Flag-MTHFD2 or depletion of MTHFD2 were generated. Cell Counting Kit-8 and colony formation assays were used to examine the effect of MTHFD2 overexpression or knockout on MCF-7 cell proliferation and clonogenicity, respectively. Luciferase reporter and an AKT inhibitor (GSK6906) analysis were carried out to investigate the effect of MTHFD2 on the AKT signaling pathway. The results demonstrated that MTHFD2 expression level was higher in breast cancer tissues compared with adjacent normal tissues. Furthermore, patients with high MTHFD2 expression had significantly poorer overall survival compared with patients with low MTHFD2 expression. In addition, ectopic expression of MTHFD2 promoted the tumorigenic properties of MCF-7 cells, including proliferation and clonogenicity. Conversely, depletion of MTHFD2 had the opposite effect on the malignant properties of MCF-7 cells. Luciferase reporter demonstrated that MTHFD2 can significantly increase the ATK luciferase density. Furthermore, the Akt inhibitor GSK690693 significantly decreased the increased clonogenicity caused by MTHFD2 overexpression in MCF-7 cells. Taken together, the findings from the present study suggested that MTHFD2 may serve a protumor role in the malignancy of breast cancer by activating the AKT signaling pathway. These results provide an alternative theoretical foundation that could help the de velopment of MTHFD2-targeted breast cancer treatment.

PMID:34007312 | PMC:PMC8120508 | DOI:10.3892/etm.2021.10135

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