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

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.

Study details

Article type

Original Research

Disease / injury model

Cancer cell lines (in vitro)

Dose comparison

Cell proliferation was measured under 0%, 5%, and 10% hydrogen gas, showing a dose-dependent increase in proliferation in responder cell lines.

Dose-dependent effect

Yes

Outcome

Positive

Findings

Hydrogen gas exposure (5% and 10%) enhanced proliferation in four out of seven human cancer cell lines, specifically those with high mitochondrial ETC activity and a readily inducible mitochondrial unfolded protein response (mtUPR). The effect was independent of basal ROS levels and was associated with increased expression of mtUPR-related molecules (ATF5, p-eIF2α, HSP60). Hydrogen also rescued proliferation suppressed by rotenone in these responder cell lines.