A gonadotropin-releasing hormone-II antagonist induces autophagy of prostate cancer cells.
Gonadotropin-releasing hormone-I (GnRH-I) is known to directly regulate prostate cancer cell proliferation. However, the role of GnRH-II in prostate cancer is unclear. Here, we investigated the effect of the GnRH-II antagonist trptorelix-1 (Trp-1) on growth of PC3 prostate cancer cells. Trp-1 induced growth inhibition of PC3 cells in vitro and inhibited growth of PC3 cells xenografted into nude mice. FITC-N3, an FITC-conjugated Trp-1 analogue, was largely present in the mitochondria of prostate cancer cells, but not in other cells that are not derived from the prostate. Trp-1-induced PC3 growth inhibition was associated with decreased mitochondrial membrane potential and increased levels of mitochondrial and cytosolic reactive oxygen species (ROS). Growth inhibition was partially prevented by cotreating cells with N-acetyl cysteine, an antioxidant. Cytochrome c release and caspase-3 activation were not detected in Trp-1-treated cells. However, Trp-1 induced autophagosome formation, as seen by increased LysoTracker staining and recruitment of microtubule-associated protein 1 light chain 3 to these new lysosomal compartments. Trp-1-induced autophagy was accompanied by decreased AKT phosphorylation and increased c-Jun NH(2) terminal kinase phosphorylation, two events known to be linked to autophagy. Taken together, these data suggest that Trp-1 directly induces mitochondrial dysfunction and ROS increase, leading to autophagy of prostate cancer cells. GnRH-II antagonists may hold promise in the treatment of prostate cancer.
Kim
Dong-Ki
DK
Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
Yang
Ji Sook
JS
Maiti
Kaushik
K
Hwang
Jong-Ik
JI
Kim
Kyungjin
K
Seen
Dongseung
D
Ahn
Younghee
Y
Lee
Cheolju
C
Kang
Byeong-Cheol
BC
Kwon
Hyuk Bang
HB
Cheon
Jun
J
Seong
Jae Young
JY
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
D009842:Oligopeptides; D017382:Reactive Oxygen Species; C539262:acetyl-(2-naphthylalanyl)(2)-4-chlorophenylalanyl-(3-pyridyl)alanyl(3)-seryl-tyrosyl-n5-aminocarbonylornithyl-tryptophyl-tyrosyl-prolyl-alaninamine; D007987:Gonadotropin-Releasing Hormone; D045304:Cytochromes c; C047717:LHRH, His(5)-Trp(7)-Tyr(8)-; D053148:Caspase 3