A gonadotropin-releasing hormone-II antagonist induces autophagy of prostate cancer cells

Kim Dong-Ki, Sook Yang Ji, Maiti Kaushik, Hwang Jong-Ik, Kim Kyungjin, Seen Dongseung, Ahn Younghee, Lee Cheolji, Kang Byeong-Cheol, Bang Kwon Hyuk, Cheon Jun, Young Seong Jae

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37 Citations (Scopus)

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-1induced autophagosome formation, as seen by increased LysoTracker staining and recruitment of microtubule-associated protein 1light 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-1directly 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.

Original languageEnglish
Pages (from-to)923-931
Number of pages9
JournalCancer Research
Volume69
Issue number3
DOIs
Publication statusPublished - 2009 Feb 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Dong-Ki, K., Ji, S. Y., Kaushik, M., Jong-Ik, H., Kyungjin, K., Dongseung, S., Younghee, A., Cheolji, L., Byeong-Cheol, K., Hyuk, B. K., Jun, C., & Jae, Y. S. (2009). A gonadotropin-releasing hormone-II antagonist induces autophagy of prostate cancer cells. Cancer Research, 69(3), 923-931. https://doi.org/10.1158/0008-5472.CAN-08-2115