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Interference with MTHFD2 induces ferroptosis in ovarian cancer cells through ERK signaling to suppress tumor malignant progression

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Abstract

Ovarian cancer (OC) is a deadliest gynecological cancer with the highest mortality rate. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a crucial tumor-promoting factor, is over-expressed in several malignancies including OC. The present study aimed to explore the role and mechanisms of MTHFD2 in OC malignant progression. Thus, cell proliferation, cycling, apoptosis, migration, and invasion were evaluated by CCK-8 assay, EdU assay, flow cytometry, wound healing, transwell assay and western blotting. Additionally, glycolysis was assessed by measuring the level of glucose and lactate production, as well as the expressions of GLUT1, HK2 and PKM2. Then the expression of ferroptosis-related proteins and ERK signaling was detected using western blotting. Ferroptosis was detected through the measurement of iron level, GSH, MDA and ROS activities. The results revealed that MTHFD2 was highly expressed in OC cells. Besides, interference with MTHFD2 induced ferroptosis, promoted ROS accumulation, destroyed mitochondrial function, reduced ATP content and inhibited glycolysis in OC cells. Subsequently, we further found that interference with MTHFD2 affected mitochondrial function and glycolysis in OC cells through ERK signaling. Moreover, interference with MTHFD2 affected ferroptosis to inhibit the malignant progression of OC cells. Collectively, our present study disclosed that interference with MTHFD2 induced ferroptosis in OC to inhibit tumor malignant progression through regulating ERK signaling.

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Data availability

The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request.

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Funding

Development and Application of Appropriate Medical and Health Technologies in Guangxi (S2022076); The excellent Medical Talents Training Program of The First Affiliated Hospital of Guangxi Medical University (2018-12-9).

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Authors and Affiliations

  1. Gynecology and Obstetrics Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China

    Xiaoliang Mo, Qianqian Liu, Kunling Liang & Yingxin Song

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  1. Xiaoliang Mo
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  2. Qianqian Liu
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XM and KL conceived and designed the study, acquired and interpreted the data. XM was a major contributor in writing the manuscript. YS and QL collected and analyzed the data. All authors read and approved the final manuscript.

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Mo, X., Liu, Q., Liang, K. et al. Interference with MTHFD2 induces ferroptosis in ovarian cancer cells through ERK signaling to suppress tumor malignant progression. J Bioenerg Biomembr (2024). https://doi.org/10.1007/s10863-024-10014-1

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