The Relationship between Clock Genes, Sirtuin 1, and Mitochondrial Activity in Head and Neck Squamous Cell Cancer: Effects of Melatonin Treatment
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AuthorRodríguez Santana, César; López Rodríguez, Alba; Martínez Ruiz, Laura; Florido Ruiz, Javier; Ramírez Casas, Yolanda; Acuña Castroviejo, Darío; Escames Rosa, Germaine
Head and neck squamous cell carcinomaChronodisruptionClock genesMelatoninMitochondria
Rodríguez-Santana, C.; López-Rodríguez, A.;Martinez-Ruiz, L.; Florido, J.; Cela, O.; Capitanio, N.; Ramírez-Casas, Y.; Acuña-Castroviejo, D.; Escames, G. The Relationship between Clock Genes, Sirtuin 1, and Mitochondrial Activity in Head and Neck Squamous Cell Cancer: Effects of Melatonin Treatment. Int. J. Mol. Sci. 2023, 24, 15030. [https://doi.org/10.3390/ijms241915030]
SponsorshipMCIN/AEI/10.13039/501100011033; Unión Europea “NextGenerationEU”/PRTR (PID2020-115112RB-I00; SAF2017-85903-P); Consejería de Universidad, Investigación e Inovación (CTS-101: Comunicación Intercelular); FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento/Proyecto ((P18-RT-32222); European Regional Development Fund (B-CTS-071-UGR18); Instituto de Salud Carlos III (Spain) through the grant CB/10/00238 (co-funded by the European Regional Development Fund/European Social Fund “Investing in your future”); University of Granada (Grant “UNETE,” UCEPP2017- 05); FPU fellowships from the Ministerio de Educación Cultura y Deporte; PFIS fellowship from the Instituto de Salud Carlos III
The circadian clock is a regulatory system, with a periodicity of approximately 24 h, which generates rhythmic changes in many physiological processes, including mitochondrial activity. Increasing evidence links chronodisruption with aberrant functionality in clock gene expression, resulting in multiple diseases such as cancer. Melatonin, whose production and secretion oscillates according to the light–dark cycle, is the principal regulator of clock gene expression. In addition, the oncostatic effects of melatonin correlate with an increase in mitochondrial activity. However, the direct links between circadian clock gene expression, mitochondrial activity, and the antiproliferative effects of melatonin in cancers, including head and neck squamous cell carcinoma (HNSCC), remain largely unknown. In this study, we analyzed the effects of melatonin on HNSCC cell lines (Cal-27 and SCC9), which were treated with 500 and 1000 M melatonin. We found that the antiproliferative effect of melatonin is not mediated by the Bmal1 clock gene. Additionally, high doses of melatonin were observed to result in resynchronization of oscillatory circadian rhythm genes (Per2 and Sirt1). Surprisingly, the resynchronizing effect of melatonin on Per2 and Sirt1 did not produce alterations in the oscillation of mitochondrial respiratory activity. These results increase our understanding of the possible antiproliferative mechanisms in melatonin in the treatment of head and neck squamous cell carcinoma and suggest that its antiproliferative effects are independent of clock genes but are directly related to mitochondrial activity.