Evidence of Nrf2/Keap1 Signaling Regulation by Mitochodria-Generated Reactive Oxygen Species in RGK1 Cells

Hiroko P Indo; Daisuke Masuda; Sompong Sriburee; Hiromu Ito; Ikuo Nakanishi; Ken-Ichiro Matsumoto; Samlee Mankhetkorn; Moragot Chatatikun; Sirirat Surinkaew; Lunla Udomwech; Fumitaka Kawakami; Takafumi Ichikawa; Hirofumi Matsui; Jitbanjong Tangpong; Hideyuki J Majima

doi:10.3390/biom13030445

Evidence of Nrf2/Keap1 Signaling Regulation by Mitochodria-Generated Reactive Oxygen Species in RGK1 Cells

Biomolecules. 2023 Feb 27;13(3):445. doi: 10.3390/biom13030445.

Authors

Hiroko P Indo^{1

2}, Daisuke Masuda^{3

4}, Sompong Sriburee^{1

5}, Hiromu Ito^{1

6}, Ikuo Nakanishi⁶, Ken-Ichiro Matsumoto⁷, Samlee Mankhetkorn⁵, Moragot Chatatikun^{8

9}, Sirirat Surinkaew^{8

10}, Lunla Udomwech¹¹, Fumitaka Kawakami^{12

13

14}, Takafumi Ichikawa^{12

13}, Hirofumi Matsui¹⁵, Jitbanjong Tangpong^{8

10}, Hideyuki J Majima^{1

2

3

8

9

10}

Affiliations

¹ Department of Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
² Amanogawa Galactic Astronomy Research Center (AGARC), Graduate School of Sciences, Kagoshima University, Kagoshima 890-0065, Japan.
³ Department of Space Environmental Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
⁴ Utilization & Engineer Department, Japan Manned Space Systems Corporation, 21-6 Tsukuba, Tsukuba 305-0047, Japan.
⁵ Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand.
⁶ Quantum RedOx Chemistry Team, Institute for Quantum Life Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, Chiba 263-8555, Japan.
⁷ Quantitative RedOx Sensing Group, Department of Radiation Regulatory Science Research, National Institute of Radiological Sciences, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan.
⁸ School of Allied Health Sciences, Walailak University, Thasala, Nakhon Si Thammarat 80160, Thailand.
⁹ Center of Excellence Research for Melioidosis and Microorganisms, Walailak University, Thasala, Nakhon Si Thammarat 80160, Thailand.
¹⁰ Research Excellence Center for Innovation and Health Products (RECIHP), School of Allied Health Sciences, Walailak University, Thasala, Nakhon Si Thammarat 80160, Thailand.
¹¹ School of Medicine, Walailak University, Thasala, Nakhon Si Thammarat 80161, Thailand.
¹² Department of Regulation Biochemistry, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Sagamihara 252-0373, Japan.
¹³ Department of Health Administration, School of Allied Health Sciences, Kitasato University, 1-15-1 Kitasato, Sagamihara 252-0373, Japan.
¹⁴ Regenerative Medicine and Cell Design Research Facility, School of Allied Health Sciences, Kitasato University, 1-15-1 Kitasato, Sagamihara 252-0373, Japan.
¹⁵ Division of Gastroenterology, Graduate School of Comprehensive Human Sciences, University Tsukuba, Tsukuba 305-8575, Japan.

Abstract

It has been known that reactive oxygen species (ROS) are generated from the mitochondrial electron transport chain (ETC). Majima et al. proved that mitochondrial ROS (mtROS) caused apoptosis for the first time in 1998 (Majima et al. J Biol Chem, 1998). It is speculated that mtROS can move out of the mitochondria and initiate cellular signals in the nucleus. This paper aims to prove this phenomenon by assessing the change in the amount of manganese superoxide dismutase (MnSOD) by MnSOD transfection. Two cell lines of the same genetic background, of which generation of mtROS are different, i.e., the mtROS are more produced in RGK1, than in that of RGM1, were compared to analyze the cellular signals. The results of immunocytochemistry staining showed increase of Nrf2, Keap1, HO-1 and 2, MnSOD, GCL, GST, NQO1, GATA1, GATA3, GATA4, and GATA5 in RGK1 compared to those in RGM1. Transfection of human MnSOD in RGK1 cells showed a decrease of those signal proteins, suggesting mtROS play a role in cellular signals in nucleus.

Keywords: Nrf2/Keap1; cell signaling; gastric mucosal cells; mitochondria; reactive oxygen species; signal transduction; tumorized cells.

Publication types

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

MeSH terms

Apoptosis
Humans
Kelch-Like ECH-Associated Protein 1 / genetics
Kelch-Like ECH-Associated Protein 1 / metabolism
NF-E2-Related Factor 2* / genetics
NF-E2-Related Factor 2* / metabolism
Reactive Oxygen Species / metabolism
Signal Transduction*
Superoxide Dismutase / genetics
Superoxide Dismutase / metabolism

Substances

Reactive Oxygen Species
NF-E2-Related Factor 2
Kelch-Like ECH-Associated Protein 1
Superoxide Dismutase
KEAP1 protein, human

Grants and funding

We thank JSPS (the Japan Society for the Promotion of Science) Core-to-Core Program for supporting research.