Significance of Divergent Expression of Prostaglandin EP4 and EP3 Receptors in Human Prostate Cancer

Abstract

PGE2 has been implicated in prostate cancer tumorigenesis. We hypothesized that abnormal prostaglandin receptor (EPR) expression may contribute to prostate cancer growth. Twenty-six archived radical prostatectomy specimens were evaluated by immunohistochemistry (IHC) and Western blotting for the expression of EP1, EP2, EP3, and EP4. As a corollary, EPR expression in one normal (PZ-HPV7) and four prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) were assessed by Western blotting. Prostate cancer and normal cell growth were compared in vitro after EPR blockade, siRNA EPR knockdown, or overexpression. EP1, EP2, EP3, and EP4 receptors were detected by IHC in all areas of benign tissue within the clinical prostate cancer specimens. In areas of prostate cancer, EP4 and EP2 were overexpressed in 85% (22 of 26) and 75% (18 of 24) and EP3 expression was reduced in all (26 of 26, 100%) specimens (P < 0.05 vs. benign tissue). EP1 showed no specific differential expression pattern. Increased EP4 and reduced EP3 was confirmed by Western blotting in fresh clinical specimens and in prostate cancer cell lines (CA-HPV10, LNCaP, PC3, and Du145) compared with the normal prostate cell line (PZ-HPV7). EP2 and EP4 siRNA knockdown resulted in reduced in vitro growth and metastasis-related gene expression (MMP9 and Runx2) of prostate cancer lines, and in vitro migration was inhibited by EP4 antagonists. As a corollary, EP3-overexpressing PC3 cells displayed impaired growth in vitro. Human prostate cancer is associated with EP4 and EP2 overexpression and reduced EP3 expression. These data suggest that targeting specific EPR may represent a novel therapeutic approach for prostate cancer.

Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells

“…Consistent with these previous findings, this study as well as another recent study showed that EP3 was suppressed in prostate cancer samples compared with normal prostate samples (Huang et al 2013) and in castration-resistant cells compared with androgendependent cells. Inversely, when EP3 signaling was suppressed, LNCaP cells kept proliferating in androgendeprived conditions, similar to castration-resistant cells.…”

Silymarin suppresses the PGE2‐induced cell migration through inhibition of EP2 activation; G protein‐dependent PKA‐CREB and G protein‐independent Src‐STAT3 signal pathways

“…It has been shown that the COX-2 specific inhibitor, NS-398, and EP2 antagonist significantly suppressed migratory abilities of murine mammary tumor cells, C3L5 [38], and EP1, 2 and 4 receptor antagonists, respectively, inhibited migration of metastatic breast cancer cells, MDA-MB-231 and MCF-7 [10]. Recently, it has been also shown that PGE 2 promote migration of lung cancer cells [15], RCC [12], and prostate cancer cells [39] and that these effects are mediated through activation of EP4. In this study, we also founded that EP4 antagonist (L-161982) significantly suppressed PGE 2 -induced Caki cells migration ( Supplementary Figure 3) suggesting the pivotal role of EP4 in kidney cancer cells migration.…”

Intracrine prostaglandin E2 pro‐tumoral actions in prostate epithelial cells originate from non‐canonical pathways

“…3.1 | PGE 2 increases RWPE-1 cell proliferation in an EP receptor antagonist-sensitive manner PGE 2 is a major downstream mediator of COX-2 that promotes cellular proliferation in PC cells (Jain et al, 2008;Jiang & Dingledine, 2013;Huang et al, 2013;Madrigal-Martínez et al, 2015;Vo et al, 2013;Wang & Klein, 2007) but its effect on the proliferation of human non-malignant prostate epithelial cells is unknown. We addressed this subject through measuring the mitochondrial reduction of MTT in RWPE-1 cells incubated with 1 µM and 10 µM PGE 2 for 24 hr.…”

“…PGE 2 can directly bind to its receptors on tumor cells to regulate cell proliferation, apoptosis, migration and invasion as well as to induce tumor cells to secrete growth factors, pro‐inflammatory mediators, and angiogenic factors that stimulate angiogenesis and local inflammation (Wang & DuBois, ). Most of these PGE 2 effects have also been specifically documented in PC cells (Huang et al, ; Jain, Chakraborty, Raja, Kale, & Kundu, ; Jiang & Dingledine, ; Madrigal‐Martínez, Lucio‐Cazaña, & Fernández‐Martínez, ; Vo et al, ; Wang & Klein, ).…”

“…and angiogenic factors that stimulate angiogenesis and local inflammation (Wang & DuBois, 2013). Most of these PGE 2 effects have also been specifically documented in PC cells (Huang et al, 2013;Jain, Chakraborty, Raja, Kale, & Kundu, 2008;Jiang & Dingledine, 2013;Madrigal-Martínez, Lucio-Cazaña, & Fernández-Martínez, 2015;Vo et al, 2013;Wang & Klein, 2007).…”