butaprost and Kidney-Neoplasms

Silymarin has been known as a chemopreventive agent, and possesses multiple anti-cancer activities including induction of apoptosis, inhibition of proliferation and growth, and blockade of migration and invasion. However, whether silymarin could inhibit prostaglandin (PG) E2 -induced renal cell carcinoma (RCC) migration and what are the underlying mechanisms are not well elucidated. Here, we found that silymarin markedly inhibited PGE2 -stimulated migration. PGE2 induced G protein-dependent CREB phosphorylation via protein kinase A (PKA) signaling, and PKA inhibitor (H89) inhibited PGE2 -mediated migration. Silymarin reduced PGE2 -induced CREB phosphorylation and CRE-promoter activity. PGE2 also activated G protien-independent signaling pathways (Src and STAT3) and silymarin reduced PGE2 -induced phosphorylation of Src and STAT3. Inhibitor of Src (Saracatinib) markedly reduced PGE2 -mediated migration. We found that EP2, a PGE2 receptor, is involved in PGE2 -mediated cell migration. Down regulation of EP2 by EP2 siRNA and EP2 antagonist (AH6809) reduced PGE2 -inudced migration. In contrast, EP2 agonist (Butaprost) increased cell migration and silymarin effectively reduced butaprost-mediated cell migration. Moreover, PGE2 increased EP2 expression through activation of positive feedback mechanism, and PGE2 -induced EP2 expression, as well as basal EP2 levels, were reduced in silymarin-treated cells. Taken together, our study demonstrates that silymarin inhibited PGE2 -induced cell migration through inhibition of EP2 signaling pathways (G protein dependent PKA-CREB and G protein-independent Src-STAT3).

Topics: Alprostadil; Antioxidants; Benzodioxoles; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Movement; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Dinoprostone; Down-Regulation; Enzyme Activation; Enzyme Inhibitors; GTP-Binding Proteins; HCT116 Cells; HT29 Cells; Humans; Integrases; Kidney Neoplasms; Phosphorylation; Prostaglandin Antagonists; Quinazolines; Receptors, Prostaglandin E, EP2 Subtype; RNA Interference; RNA, Small Interfering; Signal Transduction; Silymarin; src-Family Kinases; STAT3 Transcription Factor; Wound Healing; Xanthones