ABSTRACT
Background
Metabolic alteration drives renal cell carcinoma (RCC) development, while the impact of melatonin (MLT), a neurohormone secreted during darkness, on RCC cell growth and underlying mechanisms remains unclear.
Methods
We detected concentration of metabolites through metabolomic analyses using UPLC-MS/MS, and the oxygen consumption rate was determined using the Seahorse Extracellular Flux analyzer.
Results
We observed that MLT effectively inhibited RCC cell growth both in vitro and in vivo. Additionally, MLT increased ROS levels, suppressed antioxidant enzyme activity, and induced apoptosis. Furthermore, MLT treatment upregulated key TCA cycle metabolites while reducing aerobic glycolysis products, leading to higher oxygen consumption rate, ATP production, and membrane potential. Moreover, MLT treatment suppressed phosphorylation of Akt, mTOR, and p70 S6 Kinase as well as the expression of HIF-1α/VEGFA in RCC cells; these effects were reversed by NAC (ROS inhibitors). Conversely, MLT synergistically inhibited cell growth with sunitinib and counteracted the Warburg effect induced by sunitinib in RCC cells.
Conclusions
In conclusion, our results indicate that MLT treatment reverses the Warburg effect and promotes intracellular ROS production, which leads to the suppression of Akt/mTOR/S6K signaling pathway, induction of cell apoptosis, and synergistically inhibition of cell growth with sunitinib in RCC cells. Overall, this study provides new insights into the mechanisms underlying anti-tumor effect of MLT in RCC cells, and suggests that MLT might be a promising therapeutic for RCC.
Acknowledgements
KX, YJ, and PG designed and performed the experiments, analyzed the data, and wrote the paper; JB, DZ, YC, JM and ZZ performed the experiments and analyzed the data; XW and PG coordinated and supervised the experiments.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability
The data and materials during the current study are available from the corresponding author on reasonable request.
Ethical approval
All protocols used for animal manipulation were approved by the Institutional Animal Care Committee.