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 FITCconjugated 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 Nacetyl 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. [Cancer Res 2009;69(3):923-31]

GPCRs and cancer

“…Nevertheless, GnRH analogues were shown to suppress directly the growth of endometrial, ovarian, breast and prostate tumors and uterine leiomyoma [122,127,128] . Likewise, the growth of prostate cancer cells in vitro and in tumor xenografts was inhibited by activating the GnRH receptor or by GnRH receptor blockade [129] . In line with these observations, phase III trial data have demonstrated that GnRH agonists are effective and well tolerated in the treatment of hormone-sensitive prostate cancer [130] .…”

16-hydroxy-cleroda-3,13-dien-16,15-olide induced glioma cell autophagy via ROS generation and activation of p38 MAPK and ERK-1/2

“…Certain cellular stresses, such as oxidative stress, nutrient starvation, misfolded protein accumulation, and irradiation could induce autophagy. Recent reports have shown that autophagy is also a cell death mechanism and a response to various anticancer therapies in several types of cancer cells (Chiu et al, 2009;Kim et al, 2009;Liu et al, 2010;Nahimana et al, 2009). Over several decades, the application of natural products has been shown to play an important role in the physiological function of human life, and basic research to develop clinical treatment drugs has a long history.…”

Contribution of Chicken GnRH-II and Lamprey GnRH-III on Gonadotropin Secretion

“…Antagonist for the type II GnRHR have also been developed and tested in cells expressing rat GnRH (Maiti et al, 2003), human endometrial cells (Fister et al, 2007), and mice (Kim et al, 2009). However, all of these species have lost a functional type II GnRHR (Stewart et al, 2009) and data from these experiments are questionable.…”