Abstract
PGE2, the major product of cyclooxygenases implicated in carcinogenesis, is significantly upregulated in cervical cancer. PGE2 via prostanoid receptor EP4 stimulates proliferation and motility while inhibiting apoptosis and immune surveillance. It promotes angiogenesis by stimulating the production of pro-angiogenic factors. The present study demonstrates GW627368X, a highly selective competitive EP4 antagonist, which hinders cervical cancer progression by inhibiting EP4/epithelial growth factor receptor (EGFR) interactive signaling. GW627368X reduced protein kinase A (PKA) phosphorylation which in turn leads to decreased cAMP response element-binding protein (CREB) activation. Decreased PKA phosphorylation also directly enhanced Bax activity and in part reduced glycogen synthase kinase 3 (GSK3)β phosphorylation. Owing to the interactive signaling between EP4 and EGFR, GW627368X lowered EGFR phosphorylation in turn reducing Akt, mitogen-activated protein kinase (MAPK) and GSK3β activity significantly. Sublethal dose of GW627368X was found to reduce the nuclear translocation of β-catenin in a time dependent manner along with time-dependent decrease in cytoplasmic as well as whole-cell β-catenin. Decreased CREB and β-catenin transcriptional activity restricts the aberrant transcription of key genes like EP4, cyclooxygenase (COX)-2, vascular endothelial growth factor and c-myc, which ultimately control cell survival, proliferation and angiogenesis. Reduced activity of EGFR resulted in enhanced expression of 15-hydroxyprostaglandin dehydrogenase increasing PGE2 degradation thereby blocking a positive feedback loop. In xenograft model, dose-dependent decrease in cancer proliferation was observed characterized by reduction in tumor mass and volume and a marked decrease in Ki67 expression. A diminished CD31 specific staining signified decreased tumor angiogenesis. Reduced expression of pAkt, pMAPK, pEGFR and COX-2 validated in vitro results. GW627368X therefore effectively inhibits tumor survival, motility, proliferation and angiogenesis by blocking EP4/EGFR interactive signaling. EP4 is a potent therapeutic target in cervical cancer and can be explored in combination with conventional therapies to attain superior outcomes and to overcome complications associated with organ toxicities, therapeutic resistance and disease relapse.
Highlights
COX-2 upregulation and enhanced prostaglandin E2 (PGE2) synthesis in cervical carcinoma is well known and it regulates neoplastic cell function via the EP2 and EP4 receptors.[4]
COX-2 expression is correlated with higher vascular endothelial growth factor (VEGF) expression, lymphangiogenesis and lymph node metastasis in cervical cancer.[5]
We explored the interactive signaling between EP4 prostanoid receptor and the epidermal growth factor receptor (EGFR)
Summary
COX-2 upregulation and enhanced PGE2 synthesis in cervical carcinoma is well known and it regulates neoplastic cell function via the EP2 and EP4 receptors.[4]. Binding of PGE2 to EP4 receptor stimulates adenylyl cyclase activity enhancing cyclic adenosine monophosphate production which induces the transcription of gene encoding aromatase via CREB.[8] there is increased biosynthesis of aromatase enzyme. It is important mediator in cervical carcinogenesis as the uterine cervix is highly responsive to estrogen. Folds (106) higher expression of EP4 is reported in cervical cancer compared with normal controls.[4] EP4, unlike other prostanoid receptors, associates with multiple signaling pathways involved in carcinogenesis.[9] In the present study we demonstrate EP4 prostanoid receptor as a potential therapeutic target in cervical cancer using GW627368X, a highly selective, competitive EP4 antagonist.[10] We explored the interactive signaling between EP4 prostanoid receptor and the epidermal growth factor receptor (EGFR). Activation of EGFR signaling leads to increase in MAPK activity resulting in activator protein1-mediated induction of COX-2 transcription and enhanced synthesis of PGE2.8,11,12 Stimulation of EGFR signaling inhibits expression of 15-hydroxyprostaglandin dehydrogenase, the key enzyme for catabolism of PGE2, leading to enhanced accumulation of PGE2 in the tumor vicinity due to increased production and decreased degradation
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