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:10.1038/s41420-024-01866-y

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

Cell Death Discov. 2024 Feb 27;10(1):101. doi: 10.1038/s41420-024-01866-y.

Authors

Jiyun Zhu^#^{1

2}, Zehao Yu^#³, Xuguang Wang^#⁴, Jinghui Zhang^#³, Yi Chen⁴, Kaibo Chen⁵, Bin Zhang¹, Jianhong Sun⁶, Jianshuai Jiang⁷, Siming Zheng^{8

9}

Affiliations

¹ Hepatopancreatobiliary Surgery Department, The First Affiliated Hospital of Ningbo University, Ningbo, China.
² FUJIAN Medical University, Fuzhou, China.
³ Health Science Center, Ningbo University, Ningbo, China.
⁴ Emergency Department, The First Affiliated Hospital of Ningbo University, Ningbo, China.
⁵ Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁶ Department of Traditional Chinese Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, China. jianhong1888@163.com.
⁷ Hepatopancreatobiliary Surgery Department, The First Affiliated Hospital of Ningbo University, Ningbo, China. ningbo994261504@qq.com.
⁸ Hepatopancreatobiliary Surgery Department, The First Affiliated Hospital of Ningbo University, Ningbo, China. 29010921@qq.com.
⁹ FUJIAN Medical University, Fuzhou, China. 29010921@qq.com.

^# Contributed equally.

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.