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ALEX1 Regulates Proliferation and Apoptosis in Breast Cancer Cells

  • Gao, Yue (Molecular Medicine & Cancer Research Center, Chongqing Medical University) ;
  • Wu, Jia-Yan (Molecular Medicine & Cancer Research Center, Chongqing Medical University) ;
  • Zeng, Fan (Molecular Medicine & Cancer Research Center, Chongqing Medical University) ;
  • Liu, Ge-Li (Molecular Medicine & Cancer Research Center, Chongqing Medical University) ;
  • Zhang, Han-Tao (Molecular Medicine & Cancer Research Center, Chongqing Medical University) ;
  • Yun, Hong (Foreign Language College, Chongqing Medical University) ;
  • Song, Fang-Zhou (Molecular Medicine & Cancer Research Center, Chongqing Medical University)
  • Published : 2015.04.29

Abstract

Background: Arm protein lost in epithelial cancers, on chromosome X (ALEX) is a novel subgroup within the armadillo (ARM) family, which has one or two ARM repeat domains as opposed to more than six-thirteen repeats in the classical Armadillo family members. Materials and Methods: In the study, we explore the biological functions of ALEX1 in breast cancer cells. Overexpression of ALEX1 and silencing of ALEX1 were performed with SK-BR3 and MCF-7 cell lines. Cell proliferation and colony formation assays, along with flow cytometry, were carried out to evaluate the roles of ALEX1. Results: ALEX1 overexpression in SK-BR3 breast cancer cells inhibited proliferation and induced apoptosis. Furthermore, depletion of ALEX1 in MCF-7 breast cancer cells increased proliferation and inhibited apoptosis. Additional analyses demonstrated that the overexpression of ALEX1 activated the intrinsic apoptosis cascades through up-regulating the expression of Bax, cytosol cytochrome c, active caspase-9 and active caspase-3 and down-regulating the levels of Bcl-2 and mitochondria cytochrome c. Simultaneouly, silencing of ALEX1 inhibited intrinsic apoptosis cascades through down-regulating the expression of Bax, cytosol cytochrome c, active caspase-9, and active caspase-3 and up-regulating the level of Bcl-2 and mitochondria cytochrome c. Conclusions: Our data suggest that ALEX1 as a crucial tumor suppressor gene has been involved in cell proliferation and apoptosis in breast cancer, which may serve as a novel candidate therapeutic target.

Keywords

References

  1. Bass-Zubek AE, Godsel LM, Delmar M, et al (2009). Plakophilins: multifunctional scaffolds for adhesion and signaling. Curr Opin Cell Biol, 21, 708-16. https://doi.org/10.1016/j.ceb.2009.07.002
  2. Chen J, Han H, Chen M, et al (2014). Inactivated sendai virus strain Tianjin induces apoptosis in human breast cancer MDA-MB-231 cells. Asian Pac J Cancer Prev, 15, 5023-8. https://doi.org/10.7314/APJCP.2014.15.12.5023
  3. Chen YY, Hsu MJ, Sheu JR, et al (2013). Andrographolide, a novel NF-$\kappa$B inhibitor, induces vascular smooth muscle cell apoptosis via a ceramide-p47phox-ROS signaling cascade. Evid Based Complement Alternat Med, 821813.
  4. Chen YC, Shen SC, Lee WR, et al (2002). Emodin induces apoptosis in human promyelokukemic HL-60 cells accompanied by activation of caspase-3 cascade but independent of reactive oxygen species production. Biochem Pharmacol, 64, 1713-24. https://doi.org/10.1016/S0006-2952(02)01386-2
  5. Ding Z, Jiang T, Piao Y, et al (2015). Meta-analysis of the association between APC promoter methylation and colorectal cancer. Onco Targets Ther, 19, 211-22.
  6. Goss KH, Groden J (2000). Biology of the adenomatous polyposis coli tumor suppressor. J Clin Oncol, 18, 1967-79.
  7. Hatzfeld M (1999). The armadillo family of structural proteins. Int Rev Cytol, 186, 179-224.
  8. Iseki H, Takeda A, Andoh T, et al (2010). Human arm protein lost in epithelial cancers, on chromosome X1 (ALEX1) gene is transcriptionally regulated by CREB and Wnt/$\beta$-catenin signaling. Cancer Sci, 101, 1361-66. https://doi.org/10.1111/j.1349-7006.2010.01541.x
  9. Iseki H, Takeda A, Andoh T, et al (2012). ALEX1 suppresses colony formation ability of human colorectal carcinoma cell lines. Cancer Sci, 103, 1267-71. https://doi.org/10.1111/j.1349-7006.2012.02300.x
  10. Jemal A, Bray F, Center MM, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  11. Kurochkin IV, Yonemitsu N, Funahashi SI, et al (2001). ALEX1, a novel human armadillo repeat protein that is expressed differentially in normal tissues and carcinomas. Biochem Biophys Res Commun, 280, 340-47. https://doi.org/10.1006/bbrc.2000.4125
  12. Lowe SW, Lin AW (2000). Apoptosis in cancer. Carcinogenesis, 21, 485-95. https://doi.org/10.1093/carcin/21.3.485
  13. Lopez-Gomez M, Malmierca E, de Gorgolas M, et al (2013). Cancer in developing countries: the next most preventable pandemic.The global problem of cancer. Crit Rev Oncol Hematol, 88, 117-22. https://doi.org/10.1016/j.critrevonc.2013.03.011
  14. Munemitsu S, Albert I, Souza B, et al (1995). Regulation of intracellular $\beta$-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc Natl Acad Sci USA, 92, 3046-50. https://doi.org/10.1073/pnas.92.7.3046
  15. Mou Z, Tapper AR, Gardner PD (2009). The armadillo repeatcontaining protein, ARMCX3, physically and functionally interacts with the developmental regulatory factor Sox10. J Biol Chem, 284, 13629-40. https://doi.org/10.1074/jbc.M901177200
  16. Martin MY, Evans MB, Kratt P, et al (2014). Meeting the information needs of lower income cancer survivors: results of a randomized control trial evaluating the American Cancer Society's "I can cope". J Health Commun, 19, 441-59. https://doi.org/10.1080/10810730.2013.821557
  17. Ozawa M, Terada H, Pedraza C (1995). The fourth armadillo repeat of plakoglobin ($\gamma$-catenin) is required for its high affinity binding to the cytoplasmic domains of E-cadherin and desmosomal cadherin Dsg2, and the tumor suppressor APC protein. J Biochem, 118, 1077-82. https://doi.org/10.1093/jb/118.5.1077
  18. Peifer M, Berg S, Reynolds AB (1994). A repeating amino acid motif shared by proteins with diverse cellular roles. Cell, 76, 789-91. https://doi.org/10.1016/0092-8674(94)90353-0
  19. Riggleman B, Wieschaus E, Schedl P (1989). Molecular analysis of the armadillo locus: Uniformly distributed transcripts and a protein with novel internal repeats are associated with a Drosophilasegment polarity gene. Genes Dev, 3, 96-113. https://doi.org/10.1101/gad.3.1.96
  20. Rubinfeld B, Souza B, Albert I, et al (1995). The APC protein and E-cadherin form similar but independent complexes with a-catenin, $\beta$-catenin, and plakoglobin. J Biol Chem, 270, 5549-55. https://doi.org/10.1074/jbc.270.10.5549
  21. Rubinfeld B, Albert I, Porfiri E, et al (1996). Binding of GSK3$\beta$ to the APC-$\beta$-catenin complex and regulation of complex assembly. Science, 272, 1023-26. https://doi.org/10.1126/science.272.5264.1023
  22. Serrat R, Lopez-Domenech G, Mirra S, et al (2013).The noncanonical Wnt/PKC pathway regulates mitochondrial dynamics through degradation of the arm-like domaincontaining protein Alex3. PloS One, 8, 67773. https://doi.org/10.1371/journal.pone.0067773
  23. Troyanovsky RB, Chitaev NA, et al (1996). Cadherin binding sites of plakoglobin: localization, specificity and role in targeting to adhering junctions. J Cell Sci, 109, 3069-78.
  24. Wang C, Youle RJ (2009). The role of mitochondria in apoptosis. Annu Rev Genet, 43, 95-118. https://doi.org/10.1146/annurev-genet-102108-134850
  25. Xu W, Kimelman D (2007). Mechanistic insights from structural studies of $\beta$-catenin and its binding partners. J Cell Sci, 120, 3337-44. https://doi.org/10.1242/jcs.013771
  26. Zhang F, Kong DS, Zhang ZL, et al (2013). Tetramethylpyrazine induces G0/G1 cell cycle arrest and stimulates mitochondrialmediated and caspase-dependent apoptosis through modulating ERK/p53 signaling in hepatic stellate cells in vitro. Apoptosis, 18, 135-49. https://doi.org/10.1007/s10495-012-0791-5

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