Melatonin and prostate cancer cell proliferation: interplay with castration, epidermal growth factor, and androgen sensitivity.
BACKGROUND
Potential modulatory effects of melatonin on the proliferation of androgen-sensitive LNCaP and androgen-insensitive PC-3 and DU 145 prostate cancer cells were reported recently. In this study, we investigated the effects of combined melatonin and castration on LNCaP tumor growth in vivo, the interactions between melatonin and epidermal growth factor (EGF) on LNCaP cell proliferation, and melatonin actions on the proliferation of PC-3 and DU 145 cells.


METHODS
Tumor development and growth in castrated nude mice inoculated with LNCaP cells or in intact animals inoculated with DU 145 cells, with or without daily melatonin treatment, were monitored by observation and caliper measurement. MT(1) receptor expression in native or transfected prostate cancer cell lines was examined by immunocytochemistry or 2-[(125)I]iodomelatonin binding. Cyclin D1 expression in LNCaP cells was assessed by Western blotting, and cell proliferation was measured by thymidine incorporation and/or cell count.


RESULTS
Melatonin treatment was associated with further decreases in LNCaP tumor incidence and growth rate in castrated nude mice. Melatonin and 2-iodomelatonin (a melatonin receptor agonist) attenuated EGF-stimulated increases in LNCaP cell proliferation and cyclin D1 levels. Melatonin had no effect on the proliferation or growth of MT(1) receptor-expressing DU 145 cells, and of PC-3 cells in which MT(1) receptor protein was undetectable. The proliferation of transfected PC-3 cells expressing MT(1) receptor was unaffected by 2-iodomelatonin.


CONCLUSIONS
Together with previous data, the present results indicate synergistic action of melatonin and castration in inhibiting the growth of androgen-sensitive LNCaP tumor. Androgen-sensitive prostate cancer cell proliferation may be modulated by opposite changes in cyclin D1 levels induced by activated MT(1) and EGF receptors. In androgen-insensitive prostate cancer cells, MT(1) receptor-mediated signal transduction may become defective not only through changes in membrane receptor protein expression and/or functions, but also by means of alterations in downstream postreceptor signaling events.
Siu
Stephanie W F
SW
Department of Physiology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China. sywshiu@hkucc.hku.hk
Lau
Kai W
KW
Tam
Po C
PC
Shiu
Stephen Y W
SY
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D044094:Receptors, Melatonin; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000728:Androgens; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D019938:Cyclin D1; D004815:Epidermal Growth Factor; C044556:2-iodomelatonin; D066246:ErbB Receptors; D008550:Melatonin