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

Abstract

Although numerous epidemiological studies show aspirin to reduce risk of prostate cancer, the mechanism of this effect is unclear. Here, we first confirmed that aspirin downregulated androgen receptor (AR) and prostate-specific antigen in prostate cancer cells. We also found that aspirin upregulated prostaglandin receptor subtype EP3 but not EP2 or EP4. The EP3 antagonist L798106 and EP3 knockdown increased AR expression and cell proliferation, whereas the EP3 agonist sulprostone decreased them, indicating that EP3 affects AR expression. Additionally, EP3 (PTGER3) transcript levels were significantly decreased in human prostate cancer tissues compared with those in normal human prostate tissues, suggesting that EP3 is important to prostate carcinogenesis. Decreased EP3 expression was also seen in castration-resistant subtype CxR cells compared with parental LNCaP cells. Finally, we found that aspirin and EP3 modulators affected prostate cancer cell growth. Taken together, aspirin suppressed LNCaP cell proliferation via EP3 signaling activation; EP3 downregulation contributed to prostate carcinogenesis and to progression from androgen-dependent prostate cancer to castration-resistant prostate cancer by regulating AR expression. In conclusion, cyclooxygenases and EP3 may represent attractive therapeutic molecular targets in androgen-dependent prostate cancer.

EP2 signaling mediates suppressive effects of celecoxib on androgen receptor expression and cell proliferation in prostate cancer

“…We previously revealed that aspirin, a classic NSAID, reduced EP2 and induced EP3 expression in prostate cancer cell lines, and that EP3 signaling has an important role in the antitumor effect of aspirin. 37 Since celecoxib similarly reduced EP2 and induced EP3 expression, EP3 signaling may also participate in the antitumor activity of celecoxib in some contexts.…”

Alkylglyceronephosphate Synthase (AGPS) Alters Lipid Signaling Pathways and Supports Chemotherapy Resistance of Glioma and Hepatic Carcinoma Cell Lines

“…Selective EP1 and EP3 agonist 19(R)-hydroxy PGE1 could restore drug resistance of HepG2/ADM, while selective EP2 agonist CAY10399 and selective EP4 agonist L-902,688 had similar effect on U87MG. PGE2 is the key in COX-2 regulating the express of multidrug resistance proteins in cancer cells (Woodward et al, 1993;Tani et al, 2001;Takaoka et al, 2008;Henderson et al, 2011;Hu et al, 2013;Kashiwagi et al, 2013). COX-2/PGE2 pathway could enhance the cancer cell cycle.…”

Nonsteroidal Anti-Inflammatory Drugs and Prostatic Diseases

“…Inflammation arising from a variety of physiological insults is thought to be a major cause and promoter of various cancers, including prostate cancer [37–40]. Inflammation of the prostate is associated with the induction of cytokines, chemokines, and growth factors, as well as COX-2, which is also overexpressed in prostate cancer [21, 41].…”

“…Inflammation of the prostate is associated with the induction of cytokines, chemokines, and growth factors, as well as COX-2, which is also overexpressed in prostate cancer [21, 41]. Given their anti-inflammatory roles in the reduction of COX activity and prostaglandin synthesis, therefore [37, 42], it has been speculated that treatment with NSAIDs might reduce the risk of prostate cancer [43]. …”