title: Apoptotic death of prostate cancer cells by a gonadotropin-releasing hormone-II antagonist.
abstract: Gonadotropin-releasing hormone-I (GnRH-I) has attracted strong attention as a hormonal therapeutic tool, particularly for androgen-dependent prostate cancer patients. However, the androgen-independency of the cancer in advanced stages has spurred researchers to look for new medical treatments. In previous reports, we developed the GnRH-II antagonist Trp-1 to inhibit proliferation and stimulate the autophagic death of various prostate cancer cells, including androgen-independent cells. We further screened many GnRH-II antagonists to identify molecules with higher efficiency. Here, we investigated the effect of SN09-2 on the growth of PC3 prostate cancer cells. SN09-2 reduced the growth of prostate cancer cells but had no effect on cells derived from other tissues. Compared with Trp-1, SN09-2 conspicuously inhibited prostate cancer cell growth, even at low concentrations. SN09-2-induced PC3 cell growth inhibition was associated with decreased membrane potential in mitochondria where the antagonist was accumulated, and increased mitochondrial and cytosolic reactive oxygen species. SN09-2 induced lactate dehydrogenase release into the media and annexin V-staining on the PC3 cell surface, suggesting that the antagonist stimulated prostate cancer cell death by activating apoptotic signaling pathways. Furthermore, cytochrome c release from mitochondria to the cytosol and caspase-3 activation occurred in a concentration- and time-dependent manner. SN09-2 also inhibited the growth of PC3 cells xenotransplanted into nude mice. These results demonstrate that SN09-2 directly induces mitochondrial dysfunction and the consequent ROS generation, leading to not only growth inhibition but also apoptosis of prostate cancer cells.
authors.affiliation: Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Sumi
authors.initials: S
authors.lastname: Park
authors.affiliation: Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Ji Man
authors.initials: JM
authors.lastname: Han
authors.affiliation: Department of Urology, School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Jun
authors.initials: J
authors.lastname: Cheon
authors.affiliation: Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
authors.affiliation: Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D006801:Humans; D045022:Lactate Dehydrogenases / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000969:Antinematodal Agents; D009842:Oligopeptides; 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)-; D045022:Lactate Dehydrogenases