Distinct mechanisms by which Nrf1 and Nrf2 as drug targets contribute to the anticancer efficacy of cisplatin on hepatoma cells

Reziyamu Wufuer; Keli Liu; Jing Feng; Meng Wang; Shaofan Hu; Feilong Chen; Shanshan Lin; Yiguo Zhang

doi:10.1016/j.freeradbiomed.2024.01.031

Distinct mechanisms by which Nrf1 and Nrf2 as drug targets contribute to the anticancer efficacy of cisplatin on hepatoma cells

Free Radic Biol Med. 2024 Mar:213:488-511. doi: 10.1016/j.freeradbiomed.2024.01.031. Epub 2024 Jan 24.

Authors

Reziyamu Wufuer¹, Keli Liu², Jing Feng³, Meng Wang⁴, Shaofan Hu⁵, Feilong Chen⁶, Shanshan Lin⁷, Yiguo Zhang⁸

Affiliations

¹ Bioengineering College and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China; Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing, 402260, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China. Electronic address: 20191901703@cqu.edu.cn.
² Bioengineering College and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China; Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing, 402260, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China. Electronic address: 202219011015@stu.cqu.edu.cn.
³ Bioengineering College and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China; Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing, 402260, China. Electronic address: 114526822@qq.com.
⁴ Bioengineering College and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China. Electronic address: mengwangkk23@sina.com.
⁵ Bioengineering College and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China. Electronic address: hufan2441@163.com.
⁶ Bioengineering College and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China; Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing, 402260, China. Electronic address: 20191901682@cqu.edu.cn.
⁷ Bioengineering College and Graduate School, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China; Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing, 402260, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China. Electronic address: 1558918420@qq.com.
⁸ Chongqing University Jiangjin Hospital, School of Medicine, Chongqing University, No. 725 Jiangzhou Avenue, Dingshan Street, Jiangjin District, Chongqing, 402260, China; The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, No. 174 Shazheng Street, Shapingba District, Chongqing, 400044, China. Electronic address: yiguozhang@cqu.edu.cn.

PMID: 38278308
DOI: 10.1016/j.freeradbiomed.2024.01.031

Abstract

Cisplatin (cis-Dichlorodiamineplatinum[II], CDDP) is generally accepted as a platinum-based alkylating agent type of the DNA-damaging anticancer drug, which is widely administrated in clinical treatment of many solid tumors. The pharmacological effect of CDDP is mainly achieved by replacing the chloride ion (Cl^-) in its structure with H₂O to form active substances with the strong electrophilic properties and then react with any nucleophilic molecules, primarily leading to genomic DNA damage and subsequent cell death. In this process, those target genes driven by the consensus electrophilic and/or antioxidant response elements (EpREs/AREs) in their promoter regions are also activated or repressed by CDDP. Thereby, we here examined the expression profiling of such genes regulated by two principal antioxidant transcription factors Nrf1 and Nrf2 (both encoded by Nfe2l1 and Nfe2l2, respectively) in diverse cellular signaling responses to this intervention. The results demonstrated distinct cellular metabolisms, molecular pathways and signaling response mechanisms by which Nrf1 and Nrf2 as the drug targets differentially contribute to the anticancer efficacy of CDDP on hepatoma cells and xenograft tumor mice. Interestingly, the role of Nrf1, rather than Nrf2, is required for the anticancer effect of CDDP, to suppress malignant behavior of HepG2 cells by differentially monitoring multi-hierarchical signaling to gene regulatory networks. To our surprise, it was found there exists a closer relationship of Nrf1α than Nrf2 with DNA repair, but the hyperactive Nrf2 in Nrf1α^-∕- cells manifests a strong correlation with its resistance to CDDP, albeit their mechanistic details remain elusive.

Keywords: Cell metabolism; Cisplatin; DNA repair; Drug resistance; Gene regulation; Nrf1; Nrf2; Redox signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Cell Line
Cisplatin / pharmacology
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Mice
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism

Substances

Cisplatin
NF-E2-Related Factor 2