Identification of EP4 as a Potential Target for the Treatment of Castration-Resistant Prostate Cancer Using a Novel Xenograft Model

Abstract

More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naïve prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC. Cancer Res; 70(4); 1606-15. ©2010 AACR.

The Prostanoid EP4 Receptor and Its Signaling Pathway

“…When EP4 was overexpressed in LNCaP human prostate cancer cells, progression of tumors occurred through androgen receptor activation. In castration-resistant prostate cancer cells, the EP4 receptor antagonist ONO-AE3-208 decreased intracellular cAMP levels in vitro and tumor growth in vivo (Terada et al, 2010). Expression of S100A8, a calcium-binding protein which is highly expressed in prostate cancer, was enhanced by PGE 2 and inhibited by both EP4-specific inhibitors.…”

“…EP4 expression was detected in human prostate cancer cell lines (Chen and HughesFulford, 2000;Wang and Klein, 2007;Swami et al, 2009) and primary cancer-derived cell culture as well as normal prostate cell culture (Swami et al, 2009). In castration-resistant prostate cancer, an advanced form of androgen-insensitive prostate cancer, expression of EP4 was upregulated during progression of castration resistance (Terada et al, 2010). PGE 2 activates cell migration of prostate cancer cells via EP4.…”

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

“…49 EP4 profiling of human breast cancer tissues is currently in progress in our laboratory to test its possible association with human breast cancer progression. Both EP2 and EP4 are linked with a G s protein and thus activation of these receptors leads to an increase in intracellular cAMP followed by activation of protein kinase A.…”

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

“…This induction is mediated through the regulation of the B-cell lymphoma-2 (Bcl-2) protein (63)(64)(65). Furthermore, 12-LOX controls G1/S-phase arrest by inhibiting Akt and mitogen-activated protein kinases and regulating the expression of nuclear factor (NF)-κB (66). A proangiogenic function for 12-LOX products has also been suggested.…”