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A novel all-trans retinoic acid derivative 4-amino‑2‑trifluoromethyl-phenyl retinate inhibits the proliferation of human hepatocellular carcinoma HepG2 cells by inducing G0/G1 cell cycle arrest and apoptosis via upregulation of p53 and ASPP1 and downregulation of iASPP.
Oncol Rep. 2016 Jul; 36(1):333-41.OR

Abstract

4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, was reported to function as a tumor inhibitor in various types of cancer cells in vitro. However, little is known concerning its antitumor effect on human hepatocellular carcinoma (HCC) HepG2 cells. The aims of the present study were to investigate the effects of ATPR on the proliferation of HepG2 cells and to explore the probable mechanisms. A series of experiments were performed following the treatment of HepG2 cells with ATRA and ATPR. MTT and plate colony formation assays were used to measure the cell viability. To confirm the influence on proliferation, flow cytometry was used to detect the distribution of the cell cycle. Apoptosis was observed by Hoechst staining and flow cytometry. In addition, to characterize the underlying molecular mechanisms, immunofluorescence was applied to observe the distribution of p53. The transcription and translation levels of p53 were analyzed by real-time quantitative RT-PCR (qRT-PCR) and western blotting. The expression levels of murine double minute 2 (MDM2), apoptosis stimulating proteins of p53 (ASPP), cell cycle- and apoptosis-associated proteins were detected by western blotting. After HepG2 cells were incubated with ATRA and ATPR, the viability of the HepG2 cells was inhibited in a dose- and time-dependent manner. As well, ATPR significantly suppressed HepG2 cell colony formation and arrested cells at the G0/G1 phase, while ATRA had no obvious effects. Both Hoechst staining and flow cytometry unveiled the apoptosis of HepG2 cells. Moreover, the fluorescent density of p53 was higher in the nuclei after exposure to ATPR than that in the ATRA group. HepG2 cells treated with ATPR showed elevated mRNA and protein levels of p53 when compared with these levels in the ATRA-treated cells. Western blotting showed that ATPR increased ASPP1, p21 and Bax expression and decreased MDM2, iASPP, cyclin D and E, cyclin-dependent kinase 6 (CDK6) and Bcl-2 expression, while CDK4 and ASPP2 expression were scarcely altered. Consequently, ATPR exerted a better inhibitory effect on the proliferation of HepG2 cells than ATRA through increased expression of p53 and ASPP1 and downregulation of iASPP, thereby resulting in G0/G1 cell cycle arrest and apoptosis.

Authors+Show Affiliations

Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China.College of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China.Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China.Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China.Key Laboratory of Gene Research of Anhui Province, Anhui Medical University, Hefei, Anhui 230032, P.R. China.Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27177208

Citation

Liu, Hui, et al. "A Novel All-trans Retinoic Acid Derivative 4-amino‑2‑trifluoromethyl-phenyl Retinate Inhibits the Proliferation of Human Hepatocellular Carcinoma HepG2 Cells By Inducing G0/G1 Cell Cycle Arrest and Apoptosis Via Upregulation of P53 and ASPP1 and Downregulation of IASPP." Oncology Reports, vol. 36, no. 1, 2016, pp. 333-41.
Liu H, Chen F, Zhang L, et al. A novel all-trans retinoic acid derivative 4-amino‑2‑trifluoromethyl-phenyl retinate inhibits the proliferation of human hepatocellular carcinoma HepG2 cells by inducing G0/G1 cell cycle arrest and apoptosis via upregulation of p53 and ASPP1 and downregulation of iASPP. Oncol Rep. 2016;36(1):333-41.
Liu, H., Chen, F., Zhang, L., Zhou, Q., Gui, S., & Wang, Y. (2016). A novel all-trans retinoic acid derivative 4-amino‑2‑trifluoromethyl-phenyl retinate inhibits the proliferation of human hepatocellular carcinoma HepG2 cells by inducing G0/G1 cell cycle arrest and apoptosis via upregulation of p53 and ASPP1 and downregulation of iASPP. Oncology Reports, 36(1), 333-41. https://doi.org/10.3892/or.2016.4795
Liu H, et al. A Novel All-trans Retinoic Acid Derivative 4-amino‑2‑trifluoromethyl-phenyl Retinate Inhibits the Proliferation of Human Hepatocellular Carcinoma HepG2 Cells By Inducing G0/G1 Cell Cycle Arrest and Apoptosis Via Upregulation of P53 and ASPP1 and Downregulation of IASPP. Oncol Rep. 2016;36(1):333-41. PubMed PMID: 27177208.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel all-trans retinoic acid derivative 4-amino‑2‑trifluoromethyl-phenyl retinate inhibits the proliferation of human hepatocellular carcinoma HepG2 cells by inducing G0/G1 cell cycle arrest and apoptosis via upregulation of p53 and ASPP1 and downregulation of iASPP. AU - Liu,Hui, AU - Chen,Feihu, AU - Zhang,Ling, AU - Zhou,Qing, AU - Gui,Shuyu, AU - Wang,Yuan, Y1 - 2016/05/09/ PY - 2015/12/27/received PY - 2016/01/21/accepted PY - 2016/5/14/entrez PY - 2016/5/14/pubmed PY - 2017/3/9/medline SP - 333 EP - 41 JF - Oncology reports JO - Oncol. Rep. VL - 36 IS - 1 N2 - 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, was reported to function as a tumor inhibitor in various types of cancer cells in vitro. However, little is known concerning its antitumor effect on human hepatocellular carcinoma (HCC) HepG2 cells. The aims of the present study were to investigate the effects of ATPR on the proliferation of HepG2 cells and to explore the probable mechanisms. A series of experiments were performed following the treatment of HepG2 cells with ATRA and ATPR. MTT and plate colony formation assays were used to measure the cell viability. To confirm the influence on proliferation, flow cytometry was used to detect the distribution of the cell cycle. Apoptosis was observed by Hoechst staining and flow cytometry. In addition, to characterize the underlying molecular mechanisms, immunofluorescence was applied to observe the distribution of p53. The transcription and translation levels of p53 were analyzed by real-time quantitative RT-PCR (qRT-PCR) and western blotting. The expression levels of murine double minute 2 (MDM2), apoptosis stimulating proteins of p53 (ASPP), cell cycle- and apoptosis-associated proteins were detected by western blotting. After HepG2 cells were incubated with ATRA and ATPR, the viability of the HepG2 cells was inhibited in a dose- and time-dependent manner. As well, ATPR significantly suppressed HepG2 cell colony formation and arrested cells at the G0/G1 phase, while ATRA had no obvious effects. Both Hoechst staining and flow cytometry unveiled the apoptosis of HepG2 cells. Moreover, the fluorescent density of p53 was higher in the nuclei after exposure to ATPR than that in the ATRA group. HepG2 cells treated with ATPR showed elevated mRNA and protein levels of p53 when compared with these levels in the ATRA-treated cells. Western blotting showed that ATPR increased ASPP1, p21 and Bax expression and decreased MDM2, iASPP, cyclin D and E, cyclin-dependent kinase 6 (CDK6) and Bcl-2 expression, while CDK4 and ASPP2 expression were scarcely altered. Consequently, ATPR exerted a better inhibitory effect on the proliferation of HepG2 cells than ATRA through increased expression of p53 and ASPP1 and downregulation of iASPP, thereby resulting in G0/G1 cell cycle arrest and apoptosis. SN - 1791-2431 UR - https://www.unboundmedicine.com/medline/citation/27177208/A_novel_all_trans_retinoic_acid_derivative_4_amino‑2‑trifluoromethyl_phenyl_retinate_inhibits_the_proliferation_of_human_hepatocellular_carcinoma_HepG2_cells_by_inducing_G0/G1_cell_cycle_arrest_and_apoptosis_via_upregulation_of_p53_and_ASPP1_and_downregulation_of_iASPP_ L2 - http://www.spandidos-publications.com/or/36/1/333 DB - PRIME DP - Unbound Medicine ER -