Molecular Hydrogen Enhances Proliferation of Cancer Cells That Exhibit Potent Mitochondrial Unfolded Protein Response.

Tomoya Hasegawa,Shuto Negishi,Masaki Teranishi,Kinji Ohno,Satoru Hasegawa,Mikako Ito,Koki Takeda,Jun-Ichi Takeda,Tyler W Lebaron,Hiroshi Nishiwaki

doi:10.3390/ijms23052888

Abstract

Molecular hydrogen ameliorates pathological states in a variety of human diseases, animal models, and cell models, but the effects of hydrogen on cancer have been rarely reported. In addition, the molecular mechanisms underlying the effects of hydrogen remain mostly unelucidated. We found that hydrogen enhances proliferation of four out of seven human cancer cell lines (the responders). The proliferation-promoting effects were not correlated with basal levels of cellular reactive oxygen species. Expression profiling of the seven cells showed that the responders have higher gene expression of mitochondrial electron transport chain (ETC) molecules than the non-responders. In addition, the responders have higher mitochondrial mass, higher mitochondrial superoxide, higher mitochondrial membrane potential, and higher mitochondrial spare respiratory capacity than the non-responders. In the responders, hydrogen provoked mitochondrial unfolded protein response (mtUPR). Suppression of cell proliferation by rotenone, an inhibitor of mitochondrial ETC complex I, was rescued by hydrogen in the responders. Hydrogen triggers mtUPR and induces cell proliferation in cancer cells that have high basal and spare mitochondrial ETC activities.

Highlights

Molecular hydrogen (H2 ) can readily access any organ and cellular organelle due to its small molecular size and non-polar nature [1]
In order to examine the effects of molecular hydrogen on cancer cell growth, the proliferation of seven human cancer cell lines (A549, HCT116, HeLa, HepG2, HT1080, PC3, and SH-SY5Y cells) was analyzed by a bromodeoxyuridine (BrdU) assay after incubation for 48 h under 5% and 10% hydrogen gas, or 10% nitrogen gas
As mitochondrial unfolded protein response (mtUPR) is critical for relieving mitochondrial stress, we examined whether hydrogen alleviates mitochondrial stress provoked by rotenone, an inhibitor of mitochondrial

Summary

Introduction

Molecular hydrogen (H2 ) can readily access any organ and cellular organelle due to its small molecular size and non-polar nature [1]. Some prokaryotes carry hydrogenases to metabolize hydrogen, and some rare non-mammalian eukaryotes carry hydrogenases [2,3]. Hydrogenases do not exist in higher eukaryotes, hydrogen exerts disease-ameliorating effects in humans and rodents [4–6]. The effects of hydrogen have been repeatedly reported especially in oxidative stress, inflammatory diseases, and metabolic diseases [6]. Hydrogen was first reported to ameliorate cerebral infarction, ostensibly due to hydrogen’s ability to reduce hydroxyl radicals and peroxynitrite [7]. Subsequent studies revealed a variety of signal-modulating activities, which cannot be readily accounted for by radical scavenging activities.

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