Abstract
BackgroundThere is no consensus about the effective dosages of melatonin in cancer management, thus, it is imperative to fully understand the dose-dependent responsiveness of cancer cells to melatonin and the underlying mechanisms.MethodsHead and neck squamous cell carcinoma (HNSCC) cells with or without melatonin treatment were used as a research platform. Gene depletion was achieved by short hairpin RNA, small interfering RNA, and CRISPR/Cas9. Molecular changes and regulations were assessed by Western blotting, quantitative RT-PCR (qRT-PCR), immunohistochemistry, and chromatin Immunoprecipitation coupled with qPCR (ChIP-qPCR). The therapeutic efficacy of FGF19/FGFR4 inhibition in melatonin-mediated tumor growth and metastasis was evaluated in orthotopic tongue tumor mice.ResultsThe effect of melatonin on controlling cell motility and metastasis varies in HNSCC cells, which is dose-dependent. Mechanistically, high-dose melatonin facilitates the upregulation of FGF19 expression through activating endoplasmic stress (ER)-associated protein kinase RNA-like endoplasmic reticulum kinase (PERK)-Eukaryotic initiation factor 2 alpha (eIF2α)-activating transcription factor 4 (ATF4) pathway, which in turn promotes FGFR4-Vimentin invasive signaling and attenuates the role of melatonin in repressing metastasis. Intriguingly, following long-term exposure to high-dose melatonin, epithelial HNSCC cells revert the process towards mesenchymal transition and turn more aggressive, which is enabled by FGF19/FGFR4 upregulation and alleviated by genetic depletion of the FGF19 and FGFR4 genes or the treatment of FGFR4 inhibitor H3B-6527.ConclusionsOur study gains novel mechanistic insights into melatonin-mediated modulation of FGF19/FGFR4 signaling in HNSCC, demonstrating that activating this molecular node confines the role of melatonin in suppressing metastasis and even triggers the switch of its function from anti-metastasis to metastasis promotion. The blockade of FGF19/FGFR4 signaling would have great potential in improving the efficacy of melatonin supplements in cancer treatment.
Highlights
There is no consensus about the effective dosages of melatonin in cancer management, it is imperative to fully understand the dose-dependent responsiveness of cancer cells to melatonin and the underlying mechanisms
C-Caspase 12 was seen in cancer cells following MT exposure (Fig. 1c), suggesting that MT may ignite the apoptotic pathway through endoplasmic reticulum (ER) stress induction
To determine whether MT-induced ER stress-associated death was mediated by the mitochondrial pathway of apoptosis in Head and neck squamous cell carcinoma (HNSCC) cells, we assessed the changes in mitochondria-localized Bcl-2 family proteins in the presence or absence of MT
Summary
There is no consensus about the effective dosages of melatonin in cancer management, it is imperative to fully understand the dose-dependent responsiveness of cancer cells to melatonin and the underlying mechanisms. Induction of apoptosis and endoplasmic reticulum (ER) stress contribute to the beneficial effects of MT in cancer treatment. One of the mechanisms of the action of MT is that it functions as a potent antioxidant and free radical scavenger exhibiting sensitizing effects on ER stress-induced apoptosis in cancer cells [21]. In order for the better use of MT in the clinic, there is an urgent need for fully understanding the dose-dependent responsiveness of cancer cells to MT and the underlying mechanisms
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Journal of Experimental & Clinical Cancer Research
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
