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Structural properties of polyphenols causing cell cycle arrest at G1 phase in HCT116 human colorectal cancer cell lines.

ABSTRACT: Plant-derived polyphenols are being tested as chemopreventive agents; some polyphenols arrest the cell cycle at G1 phase, whereas others inhibit cell cycle proliferation at G2/M phase. Therefore, polyphenols have been proposed to inhibit cell cycle progression at different phases via distinct mechanisms. Indeed, our previous studies showed that small structural differences in polyphenols cause large differences in their biological activities; however, the details of the structural properties causing G1 cell cycle arrest remain unknown. In this study, we prepared 27 polyphenols, including eight different scaffolds, to gain insight into the structural conditions that arrest the cell cycle at G1 phase in a quantitative structure-activity relationship study. We used cell cycle profiles to determine the biophores responsible for G1 cell cycle arrest and believe that the biophores identified in this study will help design polyphenols that cause G1 cell cycle arrest.

SUBMITTER: Shin SY

PROVIDER: S-EPMC3759946 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Structural properties of polyphenols causing cell cycle arrest at G1 phase in HCT116 human colorectal cancer cell lines.

Shin Soon Young SY Yoon Hyuk H Ahn Seunghyun S Kim Dong-Wook DW Bae Dong-Ho DH Koh Dongsoo D Lee Young Han YH Lim Yoongho Y

International journal of molecular sciences 20130819 8

Plant-derived polyphenols are being tested as chemopreventive agents; some polyphenols arrest the cell cycle at G1 phase, whereas others inhibit cell cycle proliferation at G2/M phase. Therefore, polyphenols have been proposed to inhibit cell cycle progression at different phases via distinct mechanisms. Indeed, our previous studies showed that small structural differences in polyphenols cause large differences in their biological activities; however, the details of the structural properties cau ...[more]

PMID: 23965967

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Project description:BackgroundBursopentin (BP5) is a multifunctional pentapeptide found in the chicken bursa of Fabricius. Recent study indicated that BP5 significantly stimulates expression of p53 protein in colon cancer HCT116 cells. However, the effects and underlying mechanisms of BP5 on HCT116 cell proliferation remain largely unclear.MethodsAnalyses of cell viability, cell cycle arrest as well as apoptosis were performed to study the actions of BP5 on HCT116 cells. Western blot analyse was assayed to measure the cell cycle-related and apoptosis-related proteins. Specific siRNAs targeting IRE1, ATF-6, and PERK were used for IRE1, ATF-6, and PERK knockdown, respectively. Cellular reactive oxygen species (ROS) were detected using a H2DCF-DA green fluorescence probe. Cytosolic free Ca2+ concentrations and mitochondrial membrane potential (ΔΨm) were measured using Fluo-3 AM and JC-1 stains, respectively.ResultsBP5 possessed strong inhibitory effects on the cell growth and induced apoptosis in HCT116 cells. Mechanistically, BP5 arrested the cell cycle at G1 phase by increasing p53 and p21 expression and decreasing cyclin E1-CDK2 complex expression. BP5 treatment dramatically activated the endoplasmic reticulum (ER) stress-mediated apoptotic pathway, as revealed by the significantly enhanced expression of unfolded protein response (UPR) sensors (IRE1α, ATF6, PERK) as well as downstream signaling molecules (XBP-1s, eIF2α, ATF4 and CHOP), and by the significantly altered the BP5-induced phenotypic changes in IRE1, ATF6, and PERK knockdown cells. Additionally, BP5-induced ER stress was accompanied by the accumulation of cytosolic free Ca2+ and intracellular ROS. Furthermore, BP5 treatment resulted in the increase of Bax expression, the decrease of Bcl-2 expression and the reduction of ΔΨm, subsequently causing a release of cytochrome c from the mitochondria into the cytoplasm and finally enhancing the activities of caspase-9 and -3. In addition, z-VAD-fmk, a pan-caspase inhibitor, markedly rescued BP5-induced cell viability reduction and reduced BP5-induced apoptosis.ConclusionsOur present results suggest that BP5 has an anticancer capacity to arrest cell cycle at G1 phase and to trigger ER stress/mitochondria-mediated caspase-dependent apoptosis in HCT116 cells. Therefore, our findings provide insight into further investigations of the anticancer activities of BP5.

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Structural properties of polyphenols causing cell cycle arrest at G1 phase in HCT116 human colorectal cancer cell lines.

Publications

Structural properties of polyphenols causing cell cycle arrest at G1 phase in HCT116 human colorectal cancer cell lines.

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