LncRNA MACC1-AS1 induces gemcitabine resistance in pancreatic cancer cells through suppressing ferroptosis

Pancreatic ductal adenocarcinoma (PDA) mortality is primarily attributed to metastasis and chemotherapy resistance. In this research, the long non-coding RNA MACC1-AS1 was studied, playing a significant role in regulating lipid oxidation processes. This regulation could further lead to the inhibitio...

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Bibliographic Details
Published in:Cell death discovery 2024-02, Vol.10 (1), p.101-101, Article 101
Main Authors: Zhu, Jiyun, Yu, Zehao, Wang, Xuguang, Zhang, Jinghui, Chen, Yi, Chen, Kaibo, Zhang, Bin, Sun, Jianhong, Jiang, Jianshuai, Zheng, Siming
Format: Article
Language:English
Subjects:
631/67/1504/1713
631/67/395
Adenocarcinoma
Animal models
Antineoplastic drugs
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Chemoresistance
Chemotherapy
Cytoplasm
Drug resistance
Ferroptosis
Gemcitabine
Kinases
Life Sciences
Lipid peroxidation
Metastases
Non-coding RNA
Pancreatic cancer
Proteomics
Stem Cells
Ubiquitination
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Summary:Pancreatic ductal adenocarcinoma (PDA) mortality is primarily attributed to metastasis and chemotherapy resistance. In this research, the long non-coding RNA MACC1-AS1 was studied, playing a significant role in regulating lipid oxidation processes. This regulation could further lead to the inhibition of ferroptosis induced by chemotherapeutic drugs, making it a contributing factor to gemcitabine resistance in PDA. In both gemcitabine-resistant PDA patients and mouse models, the elevated expression level of MACC1-AS1 in the tumors was noted. Additionally, overexpression of MACC1-AS1 in pancreatic cancer cells was found to enhance tolerance to gemcitabine and suppress ferroptosis. Proteomic analysis of drug-resistant pancreatic cells revealed that overexpressed MACC1-AS1 inhibited the ubiquitination degradation of residues in the protein kinase STK33 by MDM4. Furthermore, its accumulation in the cytoplasm activated STK33, further activating the ferroptosis-suppressing proteins GPX4, thereby counteracting gemcitabine-induced cellular oxidative damage. These findings suggested that the long non-coding RNA MACC1-AS1 could play a significant role in the ability of pancreatic cancer cells to evade iron-mediated ferroptosis induced by gemcitabine. This discovery holds promise for developing clinical therapeutic strategies to combat chemotherapy resistance in pancreatic cancer.
ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-024-01866-y