The inhibitory effect of melatonin on human prostate cancer

Abstract

Prostate cancer (PCa) is one of the most commonly diagnosed human cancers in males. Nearly 191,930 new cases and 33,330 new deaths of PCa are estimated in 2020. Androgen and androgen receptor pathways played essential roles in the pathogenesis of PCa. Androgen depletion therapy is the most used therapies for primary PCa patients. However, due to the high relapse and mortality of PCa, developing novel noninvasive therapies have become the focus of research. Melatonin is an indole-like neurohormone mainly produced in the human pineal gland with a prominent anti-oxidant property. The anti-tumor ability of melatonin has been substantially confirmed and several related articles have also reported the inhibitory effect of melatonin on PCa, while reviews of this inhibitory effect of melatonin on PCa in recent 10 years are absent. Therefore, we systematically discuss the relationship between melatonin disruption and the risk of PCa, the mechanism of how melatonin inhibited PCa, and the synergistic benefits of melatonin and other drugs to summarize current understandings about the function of melatonin in suppressing human prostate cancer. We also raise several unsolved issues that need to be resolved to translate currently non-clinical trials of melatonin for clinic use. We hope this literature review could provide a solid theoretical basis for the future utilization of melatonin in preventing, diagnosing and treating human prostate cancer. Video abstract.

Keywords: ADT; AR; Melatonin; P27Kip1; Prostate cancer.

Fig. 1

Adverse effect of melatonin on the AR pathway. (1) The AR pathway. Androgen triggered the dissociation of AR and HSPs. AR and androgen formed complexes and were transported into nuclear. Nuclear AR complexes bound to the ARE region of hormone-dependent genes to start the transcription. (2) Melatonin mediated the AR nuclear exclusion via a G_i/cGMP/Ca²⁺/PKC pathway. Melatonin stimulated G_i protein to enhance the production of cGMP. cGMP induced the intracellular flux of Ca²⁺. Ca²⁺ activated PKC and PKC promoted the nuclear exclusion of AR. RGS proteins (RGS4, RGS10) exerted adverse effects on this pathway. (3) The potential involvement of G_q protein in AR nuclear exclusion. Melatonin activated phospholipase C (PLC) to generate inositoltriphosphate (IP3) and diacylglycerol (DAG) which contributed to the intracellular flux of Ca²⁺. Activated G_q protein presumably stimulated PLC or (PLD) to promote AR nuclear exclusion, and the process was inhibited by RGS4

Fig. 2

The MT1 pathway. (1) Melatonin up-regulated p27^kip1 via blocking the activity of NF-κB. MT1 receptor activated Gαs and Gαq. Gαq directly activated PKC and Gαs indirectly activated PKA via elevating cAMP. PKC and PKA inhibited the binding ability of NF-κB to the promoter region of p27^Kip1 gene. (2) Melatonin decreased the PSA level with an attenuated Ca²⁺ influx. Activated PKC inhibited the promoting effect of DHT and AR on KLK3 (PSA gene). MT1 receptor inhibited melatonin-responsive calmodulin to modulate L-type Ca²⁺ channel. (3) Melatonin interrupted the bi-directional positive interactions between AR-V7 and NF-κB. The MT 1 receptor-mediated inhibition on NF-κB decreased the formation of AR-V7 and thus blocking the interactions between AR-V7 and NF-κB

Fig. 3

Inhibition of melatonin on PCa metabolism. Melatonin can be actively transported into PCa cells via GLUT1 and thus suppressing the uptake of glucose via competing for the binding sites of GLUT1. PEPT1/2 embedded in mitochondrion membrane actively transported melatonin into mitochondrion. Melatonin can cause 10–20% decrease in ATP production via limiting the TCA cycle and cause roughly 15% decrease of lactate via inhibiting glycolysis