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Flavanones structure‐related inhibition on TPA‐induced tumor promotion through suppression of extracellular signal‐regulated protein kinases: Involvement of prostaglandin E 2 in anti‐promotive process
Author(s) -
Ko ChingHuai,
Shen ShingChuan,
Lin HuiYi,
Hou WenChi,
Lee WoanRuoh,
Yang LingLing,
Chen YenChou
Publication year - 2002
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10154
Subject(s) - flavanone , mapk/erk pathway , phosphorylation , kinase , chemistry , protein kinase a , biochemistry , flavonoid , antioxidant
Biological functions of flavanones have been studied extensively, however, the structure‐related activities of flavanones on 12‐ o ‐tetradecanoylphorbol 13‐acetate (TPA)‐induced promotive effects are still unclear. In this study, flavanone, 2′‐OH flavanone, 4′‐OH flavanone, 6‐OH flavanone showed the most significant dose‐dependent inhibition on TPA‐induced proliferative effects among eight tested flavanones in NIH3T3 cells. TPA‐induced mitogen activated protein kinases (MAPK) phosphorylation, ornithine decarboxylase (ODC), c‐Jun, and cyclooxygenase 2 (COX‐2) protein expressions in a time‐dependent manner, and the maximal inductive time point is at 1 h for MAPK phosphorylation and 6 h for others. Flavanone, 2′‐OH flavanone, 4′‐OH flavanone, 6‐OH flavanone showed the dose‐dependent inhibition on TPA‐stimulated MAPK phosphorylation, COX‐2, ODC, c‐Jun protein expressions. Induction of, prostaglandin E 2 (PGE 2 ) production was detected in TPA‐treated NIH3T3 cells, and flavanone, 2′‐OH flavanone, 4′‐OH flavanone, 6‐OH flavanone inhibited significantly PGE 2 production induced by TPA. Addition of PGE 2 reverses the inhibitory activities of flavanone, 2′‐OH flavanone, 4′‐OH flavanone, 6‐OH flavanone on TPA‐induced proliferation. And, PD98059, a specific inhibitor of ERKs, inhibited TPA‐induced MAPK phosphorylation, accompanied by decreasing COX‐2, c‐Jun, and ODC protein expression, and showed dose‐dependent inhibition on TPA‐induced proliferation in cells. These results demonstrated that PGE 2 is an important mediator in TPA‐induced proliferation, and MAPK phosphorylation was located at the upstream of COX‐2, c‐Jun, and ODC gene expressions in TPA‐induced responses. Furthermore, flavanone, 2′‐OH flavanone, 4′‐OH flavanone, 6‐OH flavanone (100 μM) suppressed TPA‐induced colony formation associated with blocking MAPK phosphorylation, ODC, c‐Jun, and COX‐2 proteins expression. And, 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) assay showed that flavanone, 2′‐OH flavanone, 4′‐OH flavanone, 6‐OH flavanone did not perform potent anti‐radical activities among these eight tested compounds. In conclusion, this study provided molecular evidences to demonstrate that flavanone, 2′‐OH flavanone, 4′‐OH flavanone, 6‐OH flavanone were potent inhibitors on TPA‐induced responses without notable cytotoxicity through suppression of PGE 2 production; and anti‐radical activity of flavanones was not correlated with preventing the occurrence of tumor promotion. We proposed that blocking TPA‐induced intracellular signaling responses might be involved in the anti‐promotive mechanism of flavanones. J. Cell. Physiol. 193: 93–102, 2002. © 2002 Wiley‐Liss, Inc.