Cell Death Discovery (Feb 2024)

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

  • Jiyun Zhu,
  • Zehao Yu,
  • Xuguang Wang,
  • Jinghui Zhang,
  • Yi Chen,
  • Kaibo Chen,
  • Bin Zhang,
  • Jianhong Sun,
  • Jianshuai Jiang,
  • Siming Zheng

DOI
https://doi.org/10.1038/s41420-024-01866-y
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 14

Abstract

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Abstract 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.