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

¹ Graduate School of Medicine, Korea University; ² School of Biological Sciences and ³ Neugex Co. Ltd., Biotechnology Incubating Center Golden Helix, Seoul National University; ⁴ Life Sciences Division, Korea Institute of Science and Technology; ⁵ Department of Experimental Animal Research, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea and ⁶ Hormone Research Center and School of Biological Sciences and Technology, Chonnam National University, Gwangju, Korea

Requests for reprints: Jae Young Seong, Graduate School of Medicine, Korea University, Seoul 136-705, Republic of Korea. Phone: 82-2-920-6090; Fax: 82-2-921-4355; E-mail: jyseong{at}korea.ac.kr.

Key Words: GnRH-II antagonist • prostate cancer • autophagy • reactive oxygen species • mitochondria

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]