Melatonin drives apoptosis in head and neck cancer by increasing mitochondrial ROS generated via reverse electron transport. Issue 3 (28th August 2022)

• Record Type: Journal Article
• Authors: Florido, Javier; Martinez‐Ruiz, Laura; Rodriguez‐Santana, César; López‐Rodríguez, Alba; Hidalgo‐Gutiérrez, Agustín; Cottet‐Rousselle, Cécile; Lamarche, Frédéric; Schlattner, Uwe; Guerra‐Librero, Ana; Aranda‐Martínez, Paula; Acuña‐Castroviejo, Darío; López, Luis C.; Escames, Germaine
• Is Part Of: Journal of pineal research. Volume 73:Issue 3(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-08-28
• Subjects: apoptosis -- head and neck cancer cells -- melatonin -- mitochondria -- oxidative damage -- reactive oxygen species -- reverse electron transport; Pineal gland -- Periodicals; Pineal Gland -- Periodicals; Épiphyse (Glande); Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 612.492
• DOI: 10.1111/jpi.12824
• Languages: English
• ISSNs: 0742-3098

Abstract

Abstract: 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.