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Biochem Biophys Res Commun. 2019 Dec 7. pii: S0006-291X(19)32315-0. doi: 10.1016/j.bbrc.2019.11.187. [Epub ahead of print]

Inhibition of LONP1 protects against erastin-induced ferroptosis in Pancreatic ductal adenocarcinoma PANC1 cells.

Author information

1
Department of Laboratory Medicine, Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: csuwanghai@163.com.
2
Center of Clinical Laboratory, Hunan Children's Hospital, Changsha, China. Electronic address: 167611005@csu.edu.cn.
3
Department of Laboratory Medicine, Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: yongxin_0452@163.com.
4
Department of Laboratory Medicine, Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: zhangwenling73@126.com.
5
Department of Laboratory Medicine, Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: xukeqian@csu.edu.cn.
6
Department of Pharmacol, Xiangya Hospital, Central South University, Changsha, China. Electronic address: lid2002@163.com.
7
Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, China. Electronic address: zhouyong421@csu.edu.cn.
8
Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, Hunan Normal University, Changsha, China. Electronic address: lihao@hunnu.edu.cn.
9
School of Pharmaceutical Science, Dalian University of Technology, Creighton University Medical Center, Dalian, China. Electronic address: xiao_gg@163.com.
10
School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China. Electronic address: lubmito@wmu.edu.cn.
11
Department of Laboratory Medicine, Third Xiangya Hospital, Central South University, Changsha, China. Electronic address: gaoge96@csu.edu.cn.

Abstract

Ferroptosis is identified as a regulated cell death mediated by iron accumulation and lipid peroxidation. The disturbances of mitochondrial morphology and function have been shown in this process. Mitochondrial Lon peptidase 1 (LONP1) is one of the main multi-function enzymes in regulating the mitochondrial function and cytological stability. To evaluate whether LONP1 take a role in ferroptosis, we applied erastin to initiate the ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Here we show that erastin triggers cell death in both of oncogenic RAS mutant PANC1 cells and wild KRAS BxPC3 cells and the expression of LONP1 was up-regulated in this process. Gene inhibition of LONP1 only negatively regulates erastin-induced cell death and the alterations of molecular indicators in PANC1 cells. Furthermore, we show that inhibition of LONP1 activates the Nrf2/Keap1 signal pathway and up-regulates the expression of GPX4, a key peroxidase in regulating ferroptosis. Together, our results uncover a previously unappreciated mechanism coupling LONP1 to ferroptosis.

KEYWORDS:

Ferroptosis; LONP1; Mitochondria; Nrf2

PMID:
31822343
DOI:
10.1016/j.bbrc.2019.11.187

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