Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells

Abstract

There is strong evidence for a role of prostaglandin E2 (PGE2) in cancer cell proliferation and tumor development. In PGE 2 biosynthesis, cyclooxygenases (COX-1/COX-2) convert arachidonic acid to PGH2, which can be isomerized to PGE2 by microsomal PGE-synthase-1 (MPGES-1). The human prostate cancer cell line DU145 expressed high amounts of MPGES-1 in a constitutive manner. MPGES-1 expression also was detectable in human prostate cancer tissues, where it appeared more abundant compared with benign hyperplasia. By using shRNA, we established stable and practically complete knockdown of MPGES-1, both in DU145 cells with high constitutive expression and in the non-small cell lung cancer cell line A549, where MPGES-1 is inducible. For microsomes prepared from knockdown clones, conversion of PGH 2 to PGE2 was reduced by 85-90%. This resulted in clear phenotypic changes: MPGES-1 knockdown conferred decreased clonogenic capacity and slower growth of xenograft tumors (with disintegrated tissue structure) in nude mice. For DU145 cells, MPGES-1 knockdown gave increased apoptosis in response to genotoxic stress (adriamycin), which could be rescued by exogenous PGE 2. The results suggest that MPGES-1 is an alternative therapeutic target in cancer cells expressing this enzyme.arachidonic acid ͉ cyclooxygenase ͉ eicosanoid ͉ prostaglandin E2

Microsomal prostaglandin E synthase-1 is involved in multiple steps of colon carcinogenesis

“…Considering that tumor cells release several cytokines and growth factors that are capable of inducing mPGES-1, such as interleukin-1b, tumor necrosis factor-a and vascular endothelial growth factor (Caso´s et al, 2011), some of these factors secreted from tumor cells may be involved in the induction of mPGES-1 in adjacent MFs. The role of cancer cell-associated mPGES-1 in tumor growth has been demonstrated in studies employing knockdown of mPGES-1 in several tumor cell lines, where its knockdown in LLC cells, the human prostate cancer cell line DU145 and the nonsmall-cell lung cancer cell line A549 reduced their growth in vitro and/or in vivo (when transplanted into mice) (Hanaka et al, 2009;Kamei et al, 2010). We recently found that, in addition to cancer cell-associated mPGES-1, host stromal cell-associated mPGES-1 contributes to tumor growth, in which LLC tumors grafted subcutaneously into mPGES-1 KO mice grew more slowly than did those grafted into WT mice, due at least in part to reduced angiogenesis .…”

“…Transgenic mice overexpressing both COX-2 and mPGES-1 developed metaplasia, hyperplasia and tumorous growth in the glandular stomach with heavy macrophage (MF) infiltration (Oshima et al, 2004(Oshima et al, , 2005. Furthermore, cell proliferation and invasive activity in vitro and xenograft formation in vivo were reduced by mPGES-1 knockdown and conversely enhanced by mPGES-1 overexpression in lung and prostate cancer cells (Hanaka et al, 2009;Kamei et al, 2010). To better evaluate the efficacy of mPGES-1 inhibition in relieving symptoms of cancer, we herein examined the effect of mPGES-1 deficiency on chemical carcinogen-induced carcinogenesis and found that the absence of mPGES-1 reduces the size and number of colorectal polyps.…”

Krüppel-like Factor 5 Transcription Factor Promotes Microsomal Prostaglandin E2 Synthase 1 Gene Transcription in Breast Cancer

“…Intriguingly, the expression of mPGES1 is elevated in a number of human cancers, including breast cancer (13). Knockdown of mPGES1 in both the DU145 prostate cancer cell line and the A549 non-small cell lung cancer cell line inhibits xenograft tumor growth in nude mice (14). mPges1 knockout mice likewise exhibit a significant reduction in both the number and size of intestinal tumors induced by an Apc mutant (15).…”

Expression and Significance of Microsomal Prostaglandin Synthase-1 (mPGES-1) and Beclin-1 in the Development of Prostate Cancer

“…Cheng et al (2006) has reported that mPGES-1 inhibitor could block PGE2 and make therapeutic effects in many diseases instead of nonsteroidal anti-inflammatory drugs (NSAIDs), meanwhile, no obvious side effects were observed. Recently, Hanaka et al (2009) has focused on the role of mPGES-1 in PCa. He found that mPGES-1 over-expressed in both PCa tissues and human PCa cell lines.…”

“…Supporting that mPGES-1 is of importance for malignant transformation and progression. Hanaka has demonstrated that there also was a significant high expression of mPGES-1 in PCa cells and high expression of mPGES-1 can promote growth and survival in the cancer cells (Hanaka et al, 2009). These results implied us that inhibition of mPGES-1 is a therapeutic option for cancers that express this enzyme.…”