The PTBP1‑NCOA4 axis promotes ferroptosis in liver cancer cells

Yang,Hao; Sun,Wensheng; Bi,Tao; Wang,Qi; Wang,Wentao; Xu,Youxin; Liu,Zhiqian; Li,Jie

doi:10.3892/or.2023.8482

The PTBP1‑NCOA4 axis promotes ferroptosis in liver cancer cells

Authors:
- Hao Yang
- Wensheng Sun
- Tao Bi
- Qi Wang
- Wentao Wang
- Youxin Xu
- Zhiqian Liu
- Jie Li
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Affiliations: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, P.R. China, Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, P.R. China, Department of Gastrointestinal Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong 264100, P.R. China
Published online on: January 13, 2023 https://doi.org/10.3892/or.2023.8482
Article Number: 45
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Polypyrimidine tract‑binding protein 1 (PTBP1) plays an important role in tumor immunity, cell proliferation, apoptosis, and autophagy by regulating RNA metabolism. However, the specific function and mechanism of PTBP1 in ferroptosis remain unclear. In the present study, it was investigated whether PTBP1 regulates ferroptosis and the exact mechanism. The iron, malondialdehyde (MDA), and GSH levels were detected in sorafenib (SF)‑treated liver cancer cells. si‑PTBP1 introduction into SF‑treated liver cancer cells resulted in a significant reduction in the levels of MDA and iron. Additionally, a significant recovery of GSH levels was observed after silencing PTBP1. StarBase v2.0 database was used to predict potential transcripts that can physically interact with PTBP1 and nuclear receptor coactivator 4 (NCOA4) mRNA was identified as the most enriched binding partner in the PTBP1‑RNA complex. A dual‑luciferase assay then demonstrated that PTBP1 directly interacted with NCOA4. PTBP1 silencing did not affect NCOA4 stability following treatment with cycloheximide. A pull‑down assay revealed that the PTBP1‑binding region was in the 5'‑UTR of the NCOA4 mRNA sequence. These results suggest that PTBP1 mediates ferroptosis in liver cancer cells by regulating NCOA4 translation. In vivo experiments reconfirmed the role of the PTBP1‑NCOA4 axis in a xenograft transplantation model. It was observed that the mean tumor weight increased after PTBP1 knockout. In conclusion, silencing of PTBP1 decreased the sensitivity of liver cancer cells to ferroptosis after SF treatment and regulated ferritinophagy by mediating NCOA4 translation.

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