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Mol. Cells 2010; 30(4): 303-310

Published online October 31, 2010

https://doi.org/10.1007/s10059-010-0119-7

© The Korean Society for Molecular and Cellular Biology

(E)-1-(3,4-Dihydroxyphenethyl)-3-Styrylurea Inhibits Proliferation of MCF-7 Cells through G1 Cell Cycle Arrest and Mitochondria-Mediated Apoptosis

Ji-Yeon Yu1,2,3, Ji-Hae Kim1, Tae-Geum Kim2, Beom-Tae Kim2, Yong-Suk Jang2,3, and Jeong-Chae Lee1,2,*

1Institute of Oral Biosciences and Brain Korea 21 Program, Chonbuk National University, Jeonju 561-756, Korea, 2Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756, Korea, 3Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju 561-756, Korea

Correspondence to : *Correspondence: leejc88@jbnu.ac.kr

Received: February 24, 2010; Revised: June 19, 2010; Accepted: June 24, 2010

Abstract

Growing interest in the beneficial effects of antioxidants has inspired the synthesis of new phenolic acid phenethyl ureas (PAPUs) with enhanced antioxidant potential. We have previously shown the capacity of one PAPU compound, (E)-1-(3,4-dihydroxyphenethyl)-3-styrylurea (PAPU1), to induce caspase-dependent apoptosis in mela-noma cells. In the present study, we examined the anti-proliferative effects of PAPU compounds on MCF-7 human breast cancer cells and determined the molecular mechanisms involved. Treatment with PAPU compounds inhibited predominantly proliferation in these cells, where the PAPU1 was the most efficient form. Flow cytometric analysis showed that PAPU1 blocked cell cycle progression in the G0/G1 phase, and reduced the proportion of cells in G2/M phase. This was related to the inhibition of cell cycle regulatory factors, including cyclin D/E and cyclin-dependent kinase (CDK) 2/4, through induction of p21Cip1. PAPU1 also induced the mitochondrial-mediated and caspase-depen-dent apoptosis in MCF-7 cells. This was evidenced by cellular changes in the levels of Bcl-2 and Bax, loss of the mitochondrial membrane potential, release of cyto-chrome c into the cytosol, and caspase-9 activation. Col-lectively, our results suggest that G1 cell cycle regulatory proteins and mitochondrial pathways are the crucial targets of PAPU1 in the chemoprevention of breast cancer cells.

Keywords caspase, G1 cell cycle arrest, MCF-7 breast cancer cells, mitochondria, phenethyl urea derivative

Article

Research Article

Mol. Cells 2010; 30(4): 303-310

Published online October 31, 2010 https://doi.org/10.1007/s10059-010-0119-7

Copyright © The Korean Society for Molecular and Cellular Biology.

(E)-1-(3,4-Dihydroxyphenethyl)-3-Styrylurea Inhibits Proliferation of MCF-7 Cells through G1 Cell Cycle Arrest and Mitochondria-Mediated Apoptosis

Ji-Yeon Yu1,2,3, Ji-Hae Kim1, Tae-Geum Kim2, Beom-Tae Kim2, Yong-Suk Jang2,3, and Jeong-Chae Lee1,2,*

1Institute of Oral Biosciences and Brain Korea 21 Program, Chonbuk National University, Jeonju 561-756, Korea, 2Department of Bioactive Material Sciences and Research Center of Bioactive Materials, Chonbuk National University, Jeonju 561-756, Korea, 3Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju 561-756, Korea

Correspondence to:*Correspondence: leejc88@jbnu.ac.kr

Received: February 24, 2010; Revised: June 19, 2010; Accepted: June 24, 2010

Abstract

Growing interest in the beneficial effects of antioxidants has inspired the synthesis of new phenolic acid phenethyl ureas (PAPUs) with enhanced antioxidant potential. We have previously shown the capacity of one PAPU compound, (E)-1-(3,4-dihydroxyphenethyl)-3-styrylurea (PAPU1), to induce caspase-dependent apoptosis in mela-noma cells. In the present study, we examined the anti-proliferative effects of PAPU compounds on MCF-7 human breast cancer cells and determined the molecular mechanisms involved. Treatment with PAPU compounds inhibited predominantly proliferation in these cells, where the PAPU1 was the most efficient form. Flow cytometric analysis showed that PAPU1 blocked cell cycle progression in the G0/G1 phase, and reduced the proportion of cells in G2/M phase. This was related to the inhibition of cell cycle regulatory factors, including cyclin D/E and cyclin-dependent kinase (CDK) 2/4, through induction of p21Cip1. PAPU1 also induced the mitochondrial-mediated and caspase-depen-dent apoptosis in MCF-7 cells. This was evidenced by cellular changes in the levels of Bcl-2 and Bax, loss of the mitochondrial membrane potential, release of cyto-chrome c into the cytosol, and caspase-9 activation. Col-lectively, our results suggest that G1 cell cycle regulatory proteins and mitochondrial pathways are the crucial targets of PAPU1 in the chemoprevention of breast cancer cells.

Keywords: caspase, G1 cell cycle arrest, MCF-7 breast cancer cells, mitochondria, phenethyl urea derivative

Mol. Cells
Aug 31, 2022 Vol.45 No.8, pp. 513~602
COVER PICTURE
Cryo-EM structure of human porphyrin transporter ABCB6 (main figure) shows that binding of hemin (inset, magenta) in concert with two glutathione molecules (cyan) primes ABCB6 for high ATP turnover (Kim et al., pp. 575-587).

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