Caffeic acid, a phenolic phytochemical in coffee, directly inhibits Fyn kinase activity and UVB-induced COX-2 expression

Abstract

Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical present in many foods, including coffee. Recent studies suggested that caffeic acid exerts anticarcinogenic effects, but little is known about the underlying molecular mechanisms and specific target proteins. In this study, we found that Fyn, one of the members of the non-receptor protein tyrosine kinase family, was required for ultraviolet (UV) B-induced cyclooxygenase-2 (COX-2) expression, and caffeic acid suppressed UVB-induced skin carcinogenesis by directly inhibiting Fyn kinase activity. Caffeic acid more effectively suppressed UVB-induced COX-2 expression and subsequent prostaglandin E 2 production in JB6 P1 mouse skin epidermal (JB6 P1) cells compared with chlorogenic acid (5-O-caffeoylquinic acid), an ester of caffeic acid with quinic acid. Data also revealed that caffeic acid more effectively induced the downregulation of COX-2 expression at the transcriptional level mediated through the inhibition of activator protein-1 (AP-1) and nuclear factor-kB transcription activity compared with chlorogenic acid. Fyn kinase activity was suppressed more effectively by caffeic acid than by chlorogenic acid, and downstream mitogen-activated protein kinases (MAPKs) were subsequently blocked. Pharmacological Fyn kinase inhibitor (3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and leflunomide) data also revealed that Fyn is involved in UVBinduced COX-2 expression mediated through the phosphorylation of MAPKs in JB6 P1 cells. Pull-down assays revealed that caffeic acid directly bound with Fyn and non-competitively with adenosine triphosphate. In vivo data from mouse skin also supported the idea that caffeic acid suppressed UVB-induced COX-2 expression by blocking Fyn kinase activity. These results suggested that this compound could act as a potent chemopreventive agent against skin cancer.

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity

“…Additional analogues of the flavone family possessing anti-kinase-mediated anticancer activity are isoflavones, which differ from flavones by the positioning of the aromatic ring in the pyrone moiety (position 3 in isoflavones as opposed to position 2 in flavones, Table 3). Well-known isoflavones are genistein (34) [54] and daidzein (33) [55]. Silibinin (35) is another example: this flavonoid targets several kinases and is currently in phase II clinical trials in prostate cancer patients [56][57][58] (Table 3).…”

“…Protocatechuic acid (3) was capable of stimulating c-Jun N-terminal kinase (JNK), another p38 MAPK, and as a consequence induced cell death in HepG2 hepatocellular carcinoma and AGS human gastric adenocarcinoma cells (Table 1) [30,31]. Caffeic and ferulic derivatives (5, 6 and 7) target specifically the PKC protein kinase family and arrest growth of various cancer cells, such as for example U937 human leukemic cells (Table 1) [18,32,33]. Caffeic acid, more specifically, inhibits directly Fyn kinase, one of the members of PKC [33].…”

Sunscreens and Antioxidants as Photo-protective Measures: An update

“…Common compounds and effects specific to each are mentioned below. * Hydroxicinnamic acids such ascaffeic or ferulic acids prevent UVB-induced erythema in vivo and in vitro, and decrease UVinduced oxidative damage in skin cells and lymphocytes [10][11][12][13]. * Polyphenolics such as flavonoids and phenolic acids, green tea polyphenols, resveratrol, astaxanthin have been found useful [14].…”

Characteristics and Applications of Bioactive Peptides in Skin Care

“…CA는 UV-B를 조사했을 때 염증관련 COX-2 발현을 농도 의존적으로 억제하며 allergy 증상의 완화에도 효과가 있는 것으로 밝혀지고 있다 [42,43]. 그러나 CA의 이러한 기능에 도 불구하고 안정성이 낮아 활용도가 적었다.…”