KRAS G12D mutation eliminates reactive oxygen species through the Nrf2/CSE/H                     <sub>2</sub>S axis and contributes to pancreatic cancer growth

Fan Kun; Zhang Shulong; Ni Xiaojian; Shen Sheng; Wang Jiwen; Sun Wentao; Suo Tao; Liu Han; Ni Xiaoling; Liu Houbao

doi:10.3724/abbs.2022173

Acta Biochimica et Biophysica Sinica (Nov 2022)

KRAS G12D mutation eliminates reactive oxygen species through the Nrf2/CSE/H <sub>2</sub>S axis and contributes to pancreatic cancer growth

Fan Kun,
Zhang Shulong,
Ni Xiaojian,
Shen Sheng,
Wang Jiwen,
Sun Wentao,
Suo Tao,
Liu Han,
Ni Xiaoling,
Liu Houbao

Affiliations

Fan Kun: ["Department of General Surgery, Central Hospital of Xuhui District, Shanghai 200032, China","Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Zhang Shulong: ["Department of General Surgery, Central Hospital of Xuhui District, Shanghai 200032, China"]
Ni Xiaojian: ["Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Shen Sheng: ["Department of General Surgery, Central Hospital of Xuhui District, Shanghai 200032, China","Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Wang Jiwen: ["Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Sun Wentao: ["Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Suo Tao: ["Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Liu Han: ["Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Ni Xiaoling: ["Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]
Liu Houbao: ["Department of General Surgery, Central Hospital of Xuhui District, Shanghai 200032, China","Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China","Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China","Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China"]

DOI: https://doi.org/10.3724/abbs.2022173
Journal volume & issue: Vol. 54
pp. 1731 – 1739

Abstract

Read online

In pancreatic cancer, KRAS G12D can trigger pancreatic cancer initiation and development. Rapid tumor growth is often accompanied by excess intracellular reactive oxygen species (ROS) production, which is unfavorable to tumor. However, the regulation of intracellular ROS levels in KRAS mutant pancreatic cancer remains unclear. In this study, we establish BxPC3 stable cell strains expressing KRAS wild type (WT) and G12D mutation and find unchanged ROS levels despite higher glycolysis and proliferation viability in KRAS mutant cells than KRAS WT cells. The key hydrogen sulfide (H 2S)-generating enzyme cystathionine-γ-lyase (CSE) is upregulated in KRAS mutant BxPC3 cells, and its knockdown significantly increases intracellular ROS levels and decreases cell glycolysis and proliferation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by KRAS mutation to promote CSE transcription. An Nrf2 binding site (‒47/‒39 bp) in the CSE promoter is verified. CSE overexpression and the addition of NaHS after Nrf2 knockdown or inhibition by brusatol decreases ROS levels and rescues cell proliferation. Our study reveals the regulatory mechanism of intracellular ROS levels in KRAS mutant pancreatic cancer cells, which provides a potential target for pancreatic cancer therapy.

Published in Acta Biochimica et Biophysica Sinica

ISSN: 1672-9145 (Print); 1745-7270 (Online)
Publisher: China Science Publishing & Media Ltd.
Country of publisher: China
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry; Science: Biology (General): Genetics
Website: https://www.sciengine.com/ABBS/home

About the journal

Abstract

Keywords