Potential involvement of mt₁ receptor and attenuated sex steroid‐induced calcium influx in the direct anti‐proliferative action of melatonin on androgen‐responsive LNCaP human prostate cancer cells

Abstract

Melatonin, a pineal secretory product, has been shown to exert a direct anti-proliferative action on the androgen-sensitive LNCaP prostate cancer cell line through hitherto undefined mechanisms. In this communication, expression of mt1 melatonin receptor protein in human prostate cancer tissues and LNCaP cells was demonstrated by immunohisto(cyto)chemistry and western blotting, hence supporting the use of LNCaP cell line as a model for the study of melatonin signaling in prostate cancer cell growth. Using 3H-thymidine incorporation assay, LNCaP cell proliferation was inhibited by 2-iodomelatonin, a high-affinity melatonin receptor agonist. Furthermore, melatonin inhibited 3H-thymidine incorporation into LNCaP cells and attenuated 5alpha-dihydrotestosterone (DHT) or 17beta-estradiol (E2)-induced stimulation of LNCaP cell proliferation at physiological and pharmacological concentrations. Similar concentration-dependent inhibition of sex steroid-induced stimulation of thymidine incorporation into LNCaP cells by 2-iodomelatonin was also observed. Interestingly, attenuation of sex steroid-stimulated calcium influx into LNCaP cells by pharmacological concentrations of melatonin was recorded, whereas 2-iodomelatonin had no effect on cytosolic calcium changes induced by sex steroids. In addition, proliferative and cytosolic calcium changes were associated with inhibition of total prostate-specific antigen (PSA) production by LNCaP cells at high physiological and pharmacological concentrations of melatonin. Our data suggest that activated mt1 receptor and attenuated sex steroid-induced calcium influx are two important mechanisms mediating the direct anti-proliferative action of melatonin on androgen-responsive human prostate cancer cells.

Melatonin triggers p53Ser phosphorylation and prevents DNA damage accumulation

“…A previous report by Xi et al (2000) showed that physiological concentrations of melatonin (for example, 0.5-5 nM) are able to reduce cell proliferation in LNCaP cells. A report from Sainz et al (2005) showed that melatonin (0.5-2 mM for 6 days) induced marked G1 arrest and S-phase reduction, but no change in cell viability was observed.…”

Melatonin Induces Apoptotic Cell Death via p53 in LNCaP Cells

“…Melatonin, a circadian indoleamine hormone secreted by the human pineal gland, is able to directly induced cell death of several types of human tumor cells [1][2][3][4][5][6][7][8][9]. Many recent reports have shown that melatonin inhibits the growth of androgen-sensitive human LNCaP prostate cancer cells [9][10][11][12]. In our previous report, we demonstrated that melatonin is able to induce apoptotic cell death in LNCaP cells via the p38 and c-JUN N-terminal kinase (JNK) pathways [13].…”

“…The MDM2 antagonist Nutlin-3 specifically inhibits proliferation of LNCaP cells through cell cycle arrest and apoptosis by increasing levels of p53-responsive p21 and MDM2 expressions, demonstrating that MDM2 antagonists retain functional p53 and androgen receptor signaling in human prostate cancers [4]. Melatonin, a circadian indoleamine hormone secreted by the human pineal gland, is able to directly induced cell death of several types of human tumor cells [1][2][3][4][5][6][7][8][9]. Many recent reports have shown that melatonin inhibits the growth of androgen-sensitive human LNCaP prostate cancer cells [9][10][11][12].…”

Melatonin as a Biomarker of Circadian Dysregulation

“…30). Several in vitro studies have reported a reduction in the growth of malignant cells and/or tumors of the breast (31)(32)(33)(34)(35) prostate (36)(37)(38)(39)(40)(41), and other tumor sites (42)(43)(44)(45)(46) by both pharmacologic and physiologic doses of melatonin. In rodent models, pinealectomy has been found to enhance tumor growth (47), and exogenous melatonin administration has shown anti-initiating (48) and oncostatic (49)(50)(51)(52) activities in various chemically induced cancers as well as in virus-transmitted tumors in mice (53).…”