A Novel All-trans Retinoid Acid Derivative Induces Apoptosis in MDA-MB-231 Breast Cancer Cells

  • Wang, Bei (Department of Pathology and Pathophysiology, medical School, Southeast University) ;
  • Yan, Yun-Wen (Laboratory of Molecular Biology, Dept of Biochemistry, Anhui Medical University) ;
  • Zhou, Qing (Laboratory of Molecular Biology, Dept of Biochemistry, Anhui Medical University) ;
  • Gui, Shu-Yu (Key Laboratory of Gene Resource Utilization for Severe Disease of Anhui Province, Anhui Medical University) ;
  • Chen, Fei-Hu (School of Pharmacy, Anhui Medical University) ;
  • Wang, Yuan (Laboratory of Molecular Biology, Dept of Biochemistry, Anhui Medical University)
  • Published : 2015.01.22


Aims: To explore the effect and probable mechanism of a synthetic retinoid 4-amino-2-tri-fluoromethylphenyl ester (ATPR) on apoptosis of MDA-MB-231 breast cancer cells. Materials and Methods: MTT assays were performed to measure the proliferation of MDA-MB-231 cells treated with different concentrations of all-trans retinoic acid (ATRA) and ATPR. Morphologic changes were observed by microscopy. The apoptosis rates and cell cycling of MDA-MB-231 cells treated with ATRA or ATPR were assessed using flow cytometry analysis. Expression of retinoic acid receptor and phosphorylation of ERK, JNK, p38 proteins were detected by Western blotting. Results: Treatment of the cells with the addition of $15{\mu}mol/L$ ATPR for 48 h clearly demonstrated reduced cell numbers and deformed cells, whereas no changes in the number and morphology were observed after treatment with ATRA. The apoptosis rate was 33.2% after breast cancer MDA-MB-231 cells were treated by ATPR ($15{\mu}mol/L$) whereas ATRA ($15{\mu}mol/L$) had no apoptotic effect. ATPR inhibited the phosphorylation of ERK, JNK, and p38 while ATRA had no significant effect. ATPR inhibited the expression of BiP and increased the expression of Chop at the protein level compared with control groups, ATRA and ATPR both decreased the protein expression of $RXR{\alpha}$, ATPR reduced the protein expression of $RAR{\beta}$ and $RXR{\beta}$ while ATRA did not decrease $RAR{\beta}$ or $RXR{\beta}$. Conclusions: ATPR could induce apoptosis of breast cancer MDA-MB-231 cells, possible mechanisms being binding to $RAR{\beta}/RXR{\beta}$ heterodimers, then activation of ER stress involving the MAPK pathway.


Supported by : National Natural Science Foundation of China, Natural Science Foundation of Anhui Province


  1. Ma J, Jemal A (2013). Breast cancer statistics. In Breast Cancer Metastasis and Drug Resistance. Springer New York, 1-18.
  2. DeSantis C, Siegel R, Bandi P, et al (2011). Breast cancer statistics. Ca-Cancer Jclin. 61, 408-18.
  3. Andres CK, Johnson R, Litton J, Phillips M, Bleyer A (2009). Breast cancer before age 40 years. Semin Oncol. 36, 237-49.
  4. Marchetti M, Russo L, Balducci D, Falanga A (2011). All trans-retinoic acid modulates the procoagulant activity of human breast cancer cells. Thromb Res, 128, 368-74.
  5. Korzeniewska D (2007). Caspases--structure and function. Europe EMC, 23, 403-7.
  6. Zhou J, L YH, Wang JR et al (2013). Gambogenic acid induction of apoptosis in a breast cancer cell Line. Asian Pac J Cancer Prev, 14, 7601-5
  7. Zhang H, Xu H, Fu WW et al (2014). 20 (S)-Protopanaxadiol induces human breast cancer MCF-7 apoptosis through a caspase-mediated pathway. Asian Pac J Cancer Prev, 15, 7919-23.
  8. Price J, Zaidi, AK, Bohensky J, et al (2010). Akt-1 mediates survival of chondrocytes from endoplasmic reticulum-induced stress. J Cell Physiol, 222, 502-8.
  9. Haydn JM, Hufnagel A, Grimm J, et al (2014). The MAPK pathway as an apoptosis enhancer in melanoma. Oncotarget, 5, 5040.
  10. Das BC, Thapa P, Karki R, et al (2014). Retinoic acid signaling pathways in development and diseases. Bioorgan Med Chem, 22, 673-83.
  11. Yung WKA, Lotan R, Lee P, Lotan D, Steck PA (1989). Modulation of growth and epidermal growth factor receptor activity by retinoic acid in human glioma cells. Cancer Res, 49, 1014-19.
  12. Wang H, Gui SY, Chen FH, Zhou Q, Wang Y (2013). New Insights into 4-amino-2-tri-fluoromethyl-phenyl ester inhibition of cell growth and migration in the A549 lung adenocarcinoma cell line. Asian Pac J Cancer Prev, 14, 7265-70.
  13. Fan TT, Cheng Y, Wang YF, et al (2014). A novel all-trans retinoid acid derivative N- (3-trifluoromethyl-phenyl)-retinamide inhibits lung adenocarcinoma a549 cell migration through down-regulating expression of myosin light chain kinase. Asian Pac J Cancer Prev, 15, 76-87.
  14. Wang B, Yan Y, Zhou J, et al (2013). A novel all-trans retinoid acid derivatives inhibits the migration of breast cancer cell lines MDA-MB-231 via myosin light chain kinase involving p38-MAPK pathway. Biomed Pharmacother, 67, 357-62.
  15. Wang N, Ge JF, Pan CX, et al (2013). Anti-tumor effect of 4-amino-2-trifluoromethyl-phenyl retinate on human breast cancer MCF-7 cells via up-regulation of retinoid receptor-induced gene-1. Biomed Pharmacother, 67, 687-92.
  16. Kaufman RJ (1999). Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev, 13, 1211-33.
  17. Kopito RR (2000). Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biology, 10, 524-30.
  18. Zhao L, Ackerman SL (2006). Endoplasmic reticulum stress in health and disease. Curr Opin cell biol, 18, 444-52.
  19. Dudek J, Benedix J, Cappel S, et al (2009). Functions and pathologies of BiP and its interaction partners. Cell Mol life Sci, 66, 1556-69.
  20. Mayer MP, Bukau B (2005). Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci, 62, 670-84.
  21. Haze K, Yoshida H, Yanagi H, Yura T, Mori K (1999). Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell, 10, 3787-99.
  22. Asada R, Kanemoto S, Kondo S, Saito A, Imaizumi K (2011). The signalling from endoplasmic reticulum-resident bZIP transcription factors involved in diverse cellular physiology. J Biochem, 149, 507-18.
  23. Harding HP, Novoa I, Zhang Y, et al (2000). Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell, 6, 1099-108.
  24. Vattem KM, Wek RC (2004). Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci USA, 101, 11269-74.
  25. Harding HP, Zhang Y, Zeng H, et al (2003). An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell, 11, 619-33.
  26. Takayanagi S, Fukuda R, Takeuchi Y, Tsukada S, Yoshida K (2013). Gene regulatory network of unfolded protein response genes in endoplasmic reticulum stress. Cell Stress Chaperon, 18, 11-23.
  27. Oyadomari S, Mori M (2003). Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ, 11, 381-9.
  28. Alizadeh, F, Bolhassani A, Khavari A, et al (2014). Retinoids and their biological effects against cancer. Int Immunopharmacol, 18, 43-9.
  29. Baumrucker CR, Schanbacher F, Shang, Y, Green MH (2006). Lactoferrin interaction with retinoid signaling: cell growth and apoptosis in mammary cells. Domest Anim Endocrin, 30, 289-303.
  30. Zhang M, Tao Y, Zhou W, et al (2014). All-trans retinoic acid induces cell-cycle arrest in human cutaneous squamous carcinoma cells by inhibiting the mitogen-activated protein kinase.activated protein 1 pathway. Clin Exp Dermatol, 39, 354-60.
  31. Olson JM, Hallahan AR (2004). p38 MAP kinase: a convergence point in cancer therapy. Trends Mol Med, 10, 125-9.