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A Gonadotropin-Releasing Hormone-II Antagonist Induces Autophagy of Prostate Cancer Cells

Authors
Kim, Dong-KiYang, Ji SookMaiti, KaushikHwang, Jong-IkKim, KyungjinSeen, DongseungAhn, YoungheeLee, CheoljuKang, Byeong-CheolKwon, Hyuk BangCheon, JunSeong, Jae Young
Issue Date
1-2월-2009
Publisher
AMER ASSOC CANCER RESEARCH
Citation
CANCER RESEARCH, v.69, no.3, pp.923 - 931
Indexed
SCIE
SCOPUS
Journal Title
CANCER RESEARCH
Volume
69
Number
3
Start Page
923
End Page
931
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/120601
DOI
10.1158/0008-5472.CAN-08-2115
ISSN
0008-5472
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 NH2 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. [Cancer Res 2009;69(3):923-31]
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