RT Journal Article
T1 Melatonin drives apoptosis in head and neck cancer by increasing mitochondrial ROS generated via reverse electron transport.
A1 Florido, Javier
A1 Martinez-Ruiz, Laura
A1 Rodriguez-Santana, Cesar
A1 Lopez-Rodriguez, Alba
A1 Hidalgo-Gutierrez, Agustin
A1 Cottet-Rousselle, Cecile
A1 Lamarche, Frederic
A1 Schlattner, Uwe
A1 Guerra-Librero, Ana
A1 Aranda-Martinez, Paula
A1 Acuña-Castroviejo, Darío
A1 Lopez, Luis C
A1 Escames, Germaine
K1 apoptosis
K1 head and neck cancer cells
K1 melatonin
K1 mitochondria
K1 oxidative damage
K1 reactive oxygen species
K1 reverse electron transport
AB The oncostatic effects of melatonin correlate with increased reactive oxygen species (ROS) levels, but how melatonin induces this ROS generation is unknown. In the present study, we aimed to elucidate the two seemingly opposing actions of melatonin regarding its relationship with free radicals. We analyzed the effects of melatonin on head and neck squamous cell carcinoma cell lines (Cal-27 and SCC-9), which were treated with 0.5 or 1 mM melatonin. We further examined the potential effects of melatonin to induce ROS and apoptosis in Cal-27 xenograft mice. Here we report that melatonin mediates apoptosis in head and neck cancer by driving mitochondrial reverse electron transport (RET) to induce ROS production. Melatonin-induced changes in tumoral metabolism led to increased mitochondrial activity, which, in turn, induced ROS-dependent mitochondrial uncoupling. Interestingly, mitochondrial complex inhibitors, including rotenone, abolished the ROS elevation indicating that melatonin increased ROS generation via RET. Melatonin also increased membrane potential and CoQ10 H2 /CoQ10 ratio to elevate mitochondrial ROS production, which are essential conditions for RET. We found that genetic manipulation of cancer cells with alternative oxidase, which transfers electrons from QH2 to oxygen, inhibited melatonin-induced ROS generation, and apoptosis. RET restored the melatonin-induced oncostatic effect, highlighting the importance of RET as the site of ROS production. These results illustrate that RET and ROS production are crucial factors in melatonin's effects in cancer cells and establish the dual effect of melatonin in protecting normal cells and inducing apoptosis in cancer cells.
PB Wiley-Blackwell Publishing, Inc.
YR 2022
FD 2022-08-16
LK http://hdl.handle.net/10668/20000
UL http://hdl.handle.net/10668/20000
LA en
NO Florido J, Martinez-Ruiz L, Rodriguez-Santana C, López-Rodríguez A, Hidalgo-Gutiérrez A, Cottet-Rousselle C, et al. Melatonin drives apoptosis in head and neck cancer by increasing mitochondrial ROS generated via reverse electron transport. J Pineal Res. 2022 Oct;73(3):e12824
NO This study was funded by grants from the MCIN/AEI/10.13039/501100011033, Spain, and the ERDF (SAF2017-85903-P, PID2020-115112RB-I00), from the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P07- CTS- 03135, P10- CTS- 5784, and CTS- 101), and from the University of Granada (Grant “UNETE,” UCE-PP2017-05), Spain. J. F. and L. M. are recipients of FPU fellowships from the Ministerio de Educación Cultura y Deporte, Spain.Some experiments on mitochondrial function were supported by the Institut Universitaire de France (to U. S.). Finally, we wish to thank San Francisco Edit (San Francisco) for proofreading the paper.
DS RISalud
RD Apr 6, 2025