GGCT Inhibits Ferroptosis in PTC Cells by Upregulating p53 Through RPS15A

ABSTRACT γ‐Glutamine cyclotransferase (GGCT) is an enzyme involved in the metabolic cycle of glutathione (GSH). Abnormal GSH metabolism is mostly related to ferroptosis. However, the mechanisms supporting aberrant GGCT expression in PTC remain to be investigated. In this study, we found that GGCT kn...

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Published inCancer science Vol. 116; no. 6; pp. 1592 - 1603
Main Authors Zhang, Hui‐min, Li, Han‐ning, Qi, Enbo, Yang, Yang, Ma, Huiping, Ma, Jie, Xiong, Xiwen, Wang, Jun, Yang, Zhi‐fang, Liao, Xing‐hua
Format Journal Article
LanguageEnglish
Published England John Wiley & Sons, Inc 01.06.2025
John Wiley and Sons Inc
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ISSN1347-9032
1349-7006
1349-7006
DOI10.1111/cas.70039

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Summary:ABSTRACT γ‐Glutamine cyclotransferase (GGCT) is an enzyme involved in the metabolic cycle of glutathione (GSH). Abnormal GSH metabolism is mostly related to ferroptosis. However, the mechanisms supporting aberrant GGCT expression in PTC remain to be investigated. In this study, we found that GGCT knockdown inhibited GSH synthesis and promoted malondialdehyde (MDA) and reactive oxygen species (ROS) accumulation, thereby promoting ferroptosis in papillary thyroid cancer cells. Pro‐GA, the specific inhibitor of GGCT, inhibited the subcutaneous tumor formation of K1 cells. IP combined with LC–MS/MS showed an interaction between GGCT and RPS15A. RPS15A is highly expressed in PTC tissues and cells, and GGCT promotes the stability of RPS15A. Knockdown of RPS15A promoted p53 expression, which in turn inhibited SLC7A11 expression, resulting in ferroptosis, while overexpression of RPS15A reversed GGCT‐induced ferroptosis. In addition, miR‐205‐5p targeted the 3’ UTR of GGCT to inhibit GGCT‐mediated ferroptosis, tumor growth, and lung metastasis. In conclusion, we found that knockdown of GGCT promoted ferroptosis in PTC cells. Mechanistically, GGCT interacts with RPS15A, and GGCT promotes the protein stability of RPS15A. Knockdown of RPS15A promotes p53 expression and inhibits SLC7A11 expression, thereby inhibiting GSH synthesis. The upstream mechanism of GGCT regulation showed that miR‐205‐5p inhibited GGCT protein expression by targeting the 3′ UTR of GGCT. Our results showed that γ‐glutamine cyclotransferase (GGCT) knockdown in PTC cells inhibited GSH synthesis, promoted the malignant accumulation of malondialdehyde (MDA) and reactive oxygen species (ROS), and finally promoted cell ferroptosis. In vivo experiments showed that Pro‐GA, a specific inhibitor of GGCT, inhibited the subcutaneous tumorigenesis of K1 cells, reduced GSH content, and promoted ROS accumulation. IP combined with LC–MS/MS showed an interaction between GGCT and RPS15A. RPS15A is highly expressed in PTC tissues and cells, and GGCT is positively correlated with the expression level of RPS15A and promotes the stability of RPS15A. Knockdown of RPS15A promoted p53 expression, which in turn inhibited SLC7A11 expression, resulting in ferroptosis, while overexpression of RPS15A reversed GGCT‐induced ferroptosis. As an upstream regulator of GGCT, miR‐205‐5p targets the 3′ UTR of GGCT to inhibit GGCT‐mediated ferroptosis, tumor growth, and lung metastasis in vitro and in vivo.
Bibliography:This study was financially supported by the National Natural Science Foundation of China (82203392), Natural Science Foundation of Hubei Province (2023AFB692), Key Scientific Research Project of Colleges and Universities in Henan Province (24A310013 to X.X.), Henan Natural Science Foundation (232300421312). Xinxiang Medical University Doctoral Start‐up Fund(505531).
Funding
Hui‐min Zhang and Han‐ning Li contributed equally to the study.
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Funding: This study was financially supported by the National Natural Science Foundation of China (82203392), Natural Science Foundation of Hubei Province (2023AFB692), Key Scientific Research Project of Colleges and Universities in Henan Province (24A310013 to X.X.), Henan Natural Science Foundation (232300421312). Xinxiang Medical University Doctoral Start‐up Fund(505531).
ISSN:1347-9032
1349-7006
1349-7006
DOI:10.1111/cas.70039