Flavanones structure-related inhibition on TPA-induced tumor promotion through suppression of extracellular signal-regulated protein kinases: Involvement of prostaglandin E2 in anti-promotive process

Ching Huai Ko, Shing Chuan Shen, Hui Yi Lin, Wen Chi Hou, Woan Ruoh Lee, Ling-Ling Yang, Yen Chou Chen

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Abstract

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 E2 (PGE2) production was detected in TPA-treated NIH3T3 cells, and fiavanone, 2COH flavanone, 2′-OH flavanone, 4′-OH flavanone, 6-OH flavanone inhibited significantly PGE2 production induced by TPA. Addition of PGE2 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 PGE2 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′-0 H fl ava none, 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 PGE2 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.

Original languageEnglish
Pages (from-to)93-102
Number of pages10
JournalJournal of Cellular Physiology
Volume193
Issue number1
DOIs
Publication statusPublished - Oct 2002

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Flavanones
Extracellular Signal-Regulated MAP Kinases
Tetradecanoylphorbol Acetate
Dinoprostone
Protein Kinases
Tumors
Acetates
Phosphorylation
Neoplasms
Mitogen-Activated Protein Kinases
Ornithine Decarboxylase
Cyclooxygenase 2
flavanone
Proto-Oncogene Proteins c-jun
Proteins
Mitogen-Activated Protein Kinase 6

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

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title = "Flavanones structure-related inhibition on TPA-induced tumor promotion through suppression of extracellular signal-regulated protein kinases: Involvement of prostaglandin E2 in anti-promotive process",
abstract = "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 E2 (PGE2) production was detected in TPA-treated NIH3T3 cells, and fiavanone, 2COH flavanone, 2′-OH flavanone, 4′-OH flavanone, 6-OH flavanone inhibited significantly PGE2 production induced by TPA. Addition of PGE2 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 PGE2 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′-0 H fl ava none, 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 PGE2 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.",
author = "Ko, {Ching Huai} and Shen, {Shing Chuan} and Lin, {Hui Yi} and Hou, {Wen Chi} and Lee, {Woan Ruoh} and Ling-Ling Yang and Chen, {Yen Chou}",
year = "2002",
month = "10",
doi = "10.1002/jcp.10154",
language = "English",
volume = "193",
pages = "93--102",
journal = "Journal of Cellular Physiology",
issn = "0021-9541",
publisher = "Wiley-Liss Inc.",
number = "1",

}

TY - JOUR

T1 - Flavanones structure-related inhibition on TPA-induced tumor promotion through suppression of extracellular signal-regulated protein kinases

T2 - Involvement of prostaglandin E2 in anti-promotive process

AU - Ko, Ching Huai

AU - Shen, Shing Chuan

AU - Lin, Hui Yi

AU - Hou, Wen Chi

AU - Lee, Woan Ruoh

AU - Yang, Ling-Ling

AU - Chen, Yen Chou

PY - 2002/10

Y1 - 2002/10

N2 - 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 E2 (PGE2) production was detected in TPA-treated NIH3T3 cells, and fiavanone, 2COH flavanone, 2′-OH flavanone, 4′-OH flavanone, 6-OH flavanone inhibited significantly PGE2 production induced by TPA. Addition of PGE2 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 PGE2 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′-0 H fl ava none, 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 PGE2 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.

AB - 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 E2 (PGE2) production was detected in TPA-treated NIH3T3 cells, and fiavanone, 2COH flavanone, 2′-OH flavanone, 4′-OH flavanone, 6-OH flavanone inhibited significantly PGE2 production induced by TPA. Addition of PGE2 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 PGE2 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′-0 H fl ava none, 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 PGE2 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.

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