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

被引:33
|
作者
Liu, Hui [1 ,2 ]
Chen, Feihu [5 ]
Zhang, Ling [1 ,2 ,6 ]
Zhou, Qing [1 ,2 ,3 ]
Gui, Shuyu [3 ,4 ]
Wang, Yuan [1 ,2 ,3 ]
机构
[1] Anhui Med Univ, Mol Biol Lab, Hefei 230032, Anhui, Peoples R China
[2] Anhui Med Univ, Dept Biochem, Hefei 230032, Anhui, Peoples R China
[3] Anhui Med Univ, Key Lab Gene Res Anhui Prov, Hefei 230032, Anhui, Peoples R China
[4] Anhui Med Univ, Affiliated Hosp 1, Dept Resp Med, Hefei 230032, Anhui, Peoples R China
[5] Anhui Med Univ, Coll Pharm, Hefei 230032, Anhui, Peoples R China
[6] Wannan Med Coll, Dept Biochem & Mol Biol, Wuhu 241002, Anhui, Peoples R China
基金
中国国家自然科学基金;
关键词
4-amino-2-trifluoromethyl-phenyl retinate; hepatocellular carcinoma HepG2 cells; p53; ASPP; proliferation; G0/G1; arrest; apoptosis; CANCER CELLS; MDM2; GENE; PROMOTES; THERAPY; GROWTH; MODULATION; COMPLEXITY; EXPRESSION; MIGRATION; STABILIZE;
D O I
10.3892/or.2016.4795
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:333 / 341
页数:9
相关论文
共 18 条
  • [11] A novel all-trans retinoic acid derivative inhibits proliferation and induces apoptosis of myelodysplastic syndromes cell line SKM-1 cells via up-regulating p53
    Du, Yan
    Li, Lan-lan
    Chen, Hao
    Wang, Cong
    Qian, Xue-wen
    Feng, Yu-bin
    Zhang, Lei
    Chen, Fei-hu
    INTERNATIONAL IMMUNOPHARMACOLOGY, 2018, 65 : 561 - 570
  • [12] All-trans retinoic acid, 1,25(OH)(2) vitamin D3 and granulocyte-macrophage colony-stimulating factor confer resistance to drug-induced apoptosis in human leukaemic blasts by inducing G0/G1 cell-cycle arrest
    Ketley, NJ
    Allen, PD
    Kelsey, SM
    Newland, AC
    BRITISH JOURNAL OF HAEMATOLOGY, 1996, 93 : 1299 - 1299
  • [13] MART-10, a novel vitamin D analog, inhibits head and neck squamous carcinoma cells growth through cell cycle arrest at G0/G1 with upregulation of p21 and p27 and downregulation of telomerase
    Chiang, Kun-Chun
    Yeh, Chun-Nan
    Hsu, Jun-Te
    Chen, Li-Wei
    Kuo, Sheng-Fong
    Sun, Chi-Chin
    Huang, Cheng-Cheng
    Pang, Jong-Hwei S.
    Flanagan, John N.
    Takano, Masashi
    Kittaka, Atsushi
    Juang, Horng-Heng
    Yang, Shih-Wei
    Chen, Tai C.
    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2013, 138 : 427 - 434
  • [14] All-trans retinoic acid, 1,25(OH)(2) vitamin D3 and granulocyte-macrophage colony-stimulating factor confer resistance to drug-induced apoptosis in human leukaemic blasts by inducing G0/G1 cell-cycle arrest.
    Ketley, NJ
    Allen, PD
    Kelsey, SM
    Newland, AC
    BRITISH JOURNAL OF HAEMATOLOGY, 1996, 93 : 247 - 247
  • [15] A synthetic coumarin derivative (4-flourophenylacetamide-acetyl coumarin) impedes cell cycle at G0/G1 stage, induces apoptosis, and inhibits metastasis via ROS-mediated p53 and AKT signaling pathways in A549 cells
    Umar, Shweta
    Soni, Rina
    Durgapal, Sunil D.
    Soman, Subhangi
    Balakrishnan, Suresh
    JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, 2020, 34 (10)
  • [16] LYG-202 inhibits the proliferation of human colorectal carcinoma HCT-116 cells through induction of G1/S cell cycle arrest and apoptosis via p53 and p21WAF1/Cip1 expression
    Liu, Wei
    Dai, Qinsheng
    Lu, Na
    Wei, Libin
    Ha, Jun
    Rong, Jingjing
    Mu, Rong
    You, Qidong
    Li, Zhiyu
    Guo, Qinglong
    BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE, 2011, 89 (03): : 287 - 298
  • [17] 2?,4?-Dihydroxy-6?-methoxy-3?,5?-dimethylchalcone and its amino acid-conjugated derivatives induce G0/G1 cell cycle arrest and apoptosis via BAX/BCL2 ratio upregulation and in silico insight in SiHa cell lines
    Utama, Kraikrit
    Khamto, Nopawit
    Meepowpan, Puttinan
    Aobchey, Paitoon
    Kantapan, Jiraporn
    Meerak, Jomkhwan
    Roytrakul, Sittiruk
    Sangthong, Padchanee
    EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2023, 184
  • [18] Anti-proliferation effect of 3-amino-2-imino-3,4-dihydro-2H-1,3-benzothiazin-4-one (BJ-601) on human vascular endothelial cells:: G0/G1 p21-associated cell cycle arrest
    Yu, CH
    Wu, J
    Su, YF
    Ho, PY
    Liang, YC
    Sheu, MT
    Lee, WS
    BIOCHEMICAL PHARMACOLOGY, 2004, 67 (10) : 1907 - 1916