Inhibition of TPA‐induced cyclooxygenase‐2 (COX‐2) expression by apigenin through downregulation of Akt signal transduction in human keratinocytes

Abstract

Apigenin is a nonmutagenic bioflavonoid that has been shown to be an inhibitor of mouse skin carcinogenesis induced by the two-stage regimen of initiation and promotion with dimethylbenzanthracene (DMBA) and 12-Otetradecanoylphorbol-13-acetate (TPA). These DMBA/TPA-induced squamous cell carcinomas overexpress cyclooxygenase-2 (COX-2). Cyclooxygenases are key enzymes required for prostaglandin (PG) synthesis, converting the arachidonic acid (AA) released by phospholipase A2 into prostaglandins. A large body of evidence indicates that the inducible form of cyclooxygenase, COX-2, is involved in tumor promotion and carcinogenesis in a wide variety of tissue types, including colon, breast, lung, and skin. In the present study, we have determined that apigenin inhibited the TPA-induced increase in COX-2 protein and mRNA in the human keratinocyte cell line; HaCaT. The induction of COX-2 elicited by TPA correlated with increased activation of Akt kinase and cell treatment with the PI3 kinase inhibitor, LY294002, blocked TPA induction of COX-2. In cells treated with TPA and apigenin, the inhibition of COX-2 expression correlated with inhibition of Akt kinase activation. Apigenin-mediated inhibition of TPA-induced COX-2 expression was reversed by transient transfection with constitutively active Akt (CA-Akt). Chemical inhibitors of MEK (PD98059), p38 (SB202190), but not JNK (SP600125) blocked TPA induction of COX-2 although apigenin did not inhibit TPA-mediated COX-2 expression through these pathways. The TPA-induced release of AA from HaCaT cells was also inhibited by cell treatment with apigenin. These data show that apigenin inhibits TPA-mediated COX-2 expression by blocking signal transduction of Akt and that apigenin also blocks AA release, which may contribute to its chemopreventive activity. ß 2005 Wiley-Liss, Inc.

Keratinocyte growth factor protects epidermis and hair follicles from cell death induced by UV irradiation, chemotherapeutic or cytotoxic agents

“…inhibitors against Erk1/2, p38 (SB203580 or SB202190), and JNK (JNK inhibitor II) at concentrations, which had been shown to be effective in keratinocytes (Park et al, 2005;Van Dross et al, 2005), we still observed a cytoprotective effect of KGF. These results demonstrate that neither MAPK signaling nor PI3K signaling is essential for the cytoprotective effect.…”

Enhancement of UVB-Induced Apoptosis by Apigenin in Human Keratinocytes and Organotypic Keratinocyte Cultures

“…HaCaT cells, a spontaneously immortalized human keratinocyte cell line, were cultured as described previously (21). HaCaT cells were 85% to 90% confluent at the time of exposure to UVB or ''sham'' irradiation followed by treatment with 0, 10, or 20 Amol/L apigenin.…”

Keratinocyte proliferation, differentiation, and apoptosis—Differential mechanisms of regulation by curcumin, EGCG and apigenin

“…Apigenin treatment reduces the number and the size of skin tumors that develop in response to chemical carcinogen or UVB exposure via a mechanism that involves inhibition of ornithine decarboxylase activity (Wei et al, 1990). Apigenin also inhibits the TPA-dependent increase in c-jun and c-fos gene expression and tumor promotion in mouse skin (Huang et al, 1997c), and suppresses TPA-mediated COX-2 expression by blocking Akt signal transduction and arachidonic acid release in HaCaT cells (Van Dross et al, 2005).…”