title: A gonadotropin-releasing hormone-II antagonist induces autophagy of prostate cancer cells.
abstract: 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.
authors.affiliation: Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Dong-Ki
authors.initials: DK
authors.lastname: Kim
authors.forename: Ji Sook
authors.initials: JS
authors.lastname: Yang
authors.forename: Kaushik
authors.initials: K
authors.lastname: Maiti
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
authors.forename: Dongseung
authors.initials: D
authors.lastname: Seen
authors.forename: Younghee
authors.initials: Y
authors.lastname: Ahn
authors.forename: Cheolju
authors.initials: C
authors.lastname: Lee
authors.forename: Byeong-Cheol
authors.initials: BC
authors.lastname: Kang
authors.forename: Hyuk Bang
authors.initials: HB
authors.lastname: Kwon
authors.forename: Jun
authors.initials: J
authors.lastname: Cheon
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
mesh_terms: 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
chemical_list: 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