Dexamethasone Disrupts Cytoskeleton Organization and Migration of T47D Human Breast Cancer Cells by Modulating the AKT/mTOR/RhoA Pathway

  • Meng, Xian-Guo (Department of Physical Medicine & Rehabilitation, Qilu Hospital, Shandong University) ;
  • Yue, Shou-Wei (Department of Physical Medicine & Rehabilitation, Qilu Hospital, Shandong University)
  • Published : 2015.01.06


Background: Glucocorticoids are commonly co-administered with chemotherapy to prevent drug-induced allergic reactions, nausea, and vomiting, and have anti-tumor functions clinically; however, the distinct effects of GC on subtypes of tumor cells, especially in breast cancer cells, are still not well understood. In this study, we aimed to clarify the effect of GC on subtypes of T47D breast cancer cells by focusing on apoptosis, cell organization and migration, and underluing molecular mechanisms. Materials and Methods: The cell scratch test was performed to observe the cell migration rate in T47D cells treated with dexamethasone (Dex). Hoechst and MTT assays were conducted to detect cell survival and rhodamine-labeled phalloidin staining to observe cytoskeleton dynamics. Related factors in the AKT/mTOR pathway were determined by Western blotting. Results: Dex treatment could effectively inhibit T47D breast cancer cell migration with disruption of the cytoskeletal dynamic organization. Moreover, the effect of Dex on cell migration and cytoskeleton may be mediated by AKT/mTOR/RhoA pathway. Although Dex inhibited T47D cell migration, it alone may not induce cell apoptosis in T47D cells. Conclusions: Dex in T47D human breast cancer cells could effectively inhibit cell migration by disrupting the cytoskeletal dynamic organization, which may be mediated by the AKT/mTOR/RhoA pathway. Our work suggests that glucocorticoid/Dex clinical use may prove helpful for the treatment of breast cancer metastasis.


  1. Alain T, Morita M, Fonseca BD, et al (2012). eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. Cancer Res, 72, 6468-76.
  2. Altomare DA, Wang HQ, Skele KL, et al (2004). AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene, 23, 5853-7.
  3. Alvarez M, Roman E, Santos ES, Raez LZ (2007). New targets for non-small-cell lung cancer therapy. Expert Rev Anticancer Ther, 7, 1423-37.
  4. Ang C, Jhaveri K, Patel D, et al (2013). Hepatic arterial infusion and systemic chemotherapy for breast cancer liver metastases. Breast J, 19, 96-9.
  5. Armstrong K, Eisen A, Weber B (2000). Assessing the risk of breast cancer. N Engl J Med, 342, 564-71.
  6. Atif F, Yousuf S, Stein DG (2014). Anti-tumor effects of progesterone in human glioblastoma multiforme: Role of PI3K/Akt/mTOR signaling. J Steroid Biochem Mol Biol, [Epub ahead of print].
  7. Banciu M, Schiffelers RM, Metselaar JM, Storm G (2008). Utility of targeted glucocorticoids in cancer therapy. J Liposome Res, 18, 47-57.
  8. Cuzick J, DeCensi A, Arun B, et al (2011). Preventive therapy for breast cancer: a consensus statement. Lancet Oncol, 12, 496-503.
  9. Frankfurt O, Rosen ST (2004). Mechanisms of glucocorticoidinduced apoptosis in hematologic malignancies: updates. Curr Opin Oncol, 16, 553-63.
  10. Fronza M, Heinzmann B, Hamburger M, et al (2009). Determination of the wound healing effect of Calendula extracts using the scratch assay with 3T3 fibroblasts. J Ethnopharmacol, 126, 463-7.
  11. Gianni L, Eiermann W, Semiglazov V, et al (2010). Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet, 375, 377-84.
  12. Graf C, Wessely N (2010). Physical activity in the prevention and therapy of breast cancer. Breast Care, 5, 389-94.
  13. Hou A, Toh LX, Gan KH, et al (2013). Rho GTPases and regulation of cell migration and polarization in human corneal epithelial cells. PLoS One, 8, 77107.
  14. Jozwiak J, Bikowska B, Grajkowska W, et al (2010). Activation of Akt/mTOR pathway in a patient with atypical teratoid/ rhabdoid tumor. Folia Neuropathol, 48, 185-9.
  15. Kostaras X, Cusano F, Kline GA, et al (2014). Use of dexamethasone in patients with high-grade glioma: a clinical practice guideline. Curr Oncol, 21, 493-503.
  16. Kumagai H, Kusaba H, Okumura Y, et al (2014). Efficacy and safety of an increased-dose of dexamethasone in patients receiving fosaprepitant chemotherapy in Japan. Asian Pac J Cancer Prev, 15, 461-5.
  17. Kurokawa M, Michelangeli VP, Findlay DM (1991). Induction of calcitonin receptor expression by glucocorticoids in T47D human breast cancer cells. J Endocrinol, 130, 321-6.
  18. Liu L, Luo Y, Chen L, et al (2010). Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity. J Biol Chem, 285, 38362-73.
  19. Lou YF, Zou ZZ, Chen PJ, et al (2014). Combination of gefitinib and DNA methylation inhibitor decitabine exerts synergistic anti-cancer activity in colon cancer cells. PLoS One, 9, 97719.
  20. Lu YS, Lien HC, Yeh PY, et al (2006a). Glucocorticoid receptor expression in advanced non-small cell lung cancer: clinicopathological correlation and in vitro effect of glucocorticoid on cell growth and chemosensitivity. Lung Cancer, 53, 303-10.
  21. Lu YS, Lien HC, Yeh PY, et al (2005). Effects of glucocorticoids on the growth and chemosensitivity of carcinoma cells are heterogeneous and require high concentration of functional glucocorticoid receptors. World J Gastroenterol, 11, 6373-80.
  22. Lu YS, Yeh PY, Chuang SE, et al (2006b). Glucocorticoids enhance cytotoxicity of cisplatin via suppression of NF-{kappa}B activation in the glucocorticoid receptor-rich human cervical carcinoma cell line SiHa. J Endocrinol, 188, 311-9.
  23. Nakayama Y, Ito Y, Tanabe M, et al (2013). A combination of aprepitant, palonosetron, and dexamethasone prevents emesis associated with anthracycline-containing regimens for patients with breast cancer. A retrospective study. Breast Cancer [Epub ahead of print].
  24. Ono M, Kawakami M, Ushikubo H (1987). Stimulation of expression of the human endogenous retrovirus genome by female steroid hormones in human breast cancer cell line T47D. J Virol, 61, 2059-62.
  25. Pal M, Koul S, Koul HK (2013). The transcription factor sterile alpha motif (SAM) pointed domain-containing ETS transcription factor (SPDEF) is required for E-cadherin expression in prostate cancer cells. J Biol Chem, 288, 12222-31.
  26. Pandurangan AK (2013). Potential targets for prevention of colorectal cancer: a focus on PI3K/Akt/mTOR and Wnt pathways. Asian Pac J Cancer Prev, 14, 2201-5.
  27. Paplomata E, O'Regan R (2014). The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol, 6, 154-66.
  28. Perlikos F, Harrington KJ, Syrigos KN (2013). Key molecular mechanisms in lung cancer invasion and metastasis: a comprehensive review. Crit Rev Oncol Hematol, 87, 1-11.
  29. Polyak K (2011). Heterogeneity in breast cancer. J Clin Invest, 121, 3786-8.
  30. Prat A, Perou CM (2011). Deconstructing the molecular portraits of breast cancer. Mol Oncol, 5, 5-23.
  31. Sau S, Banerjee R (2014). Cationic lipid-conjugated dexamethasone as a selective antitumor agent. Eur J Med Chem, 83, 433-47.
  32. Savarese A, Vecchione A (1993). Breast cancer heterogeneity assessed by flow cytometry. In Vivo, 7, 631-4.
  33. Schmidt LJ, Duncan K, Yadav N, et al (2012). RhoA as a mediator of clinically relevant androgen action in prostate cancer cells. Mol Endocrinol, 26, 716-35.
  34. Siegel R, DeSantis C, Virgo K, et al (2012). Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin, 62, 220-41.
  35. Silva AS, Kam Y, Khin ZP, et al (2012). Evolutionary approaches to prolong progression-free survival in breast cancer. Cancer Res, 72, 6362-70.
  36. Sui JQ, Xie KP, Zou W, Xie MJ (2014). Emodin inhibits breast cancer cell proliferation through the ERalpha-MAPK/Aktcyclin D1/Bcl-2 signaling pathway. Asian Pac J Cancer Prev, 15, 6247-51.
  37. Tsai WC, Tang FT, Wong MK, Pang JH (2003). Inhibition of tendon cell migration by dexamethasone is correlated with reduced alpha-smooth muscle actin gene expression: a potential mechanism of delayed tendon healing. J Orthop Res, 21, 265-71.
  38. Turnbull C, Rahman N (2008). Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet, 9, 321-45.
  39. Wang L, Yamaguchi S, Burstein MD, et al (2014). Novel somatic and germline mutations in intracranial germ cell tumours. Nature, 511, 241-5.
  40. Wu XY, Huang XE, You SX, et al (2013). Phase II study of pemetrexed as second or third line combined chemotherapy in patients with colorectal cancer. Asian Pac J Cancer Prev, 14, 2019-22.
  41. Xia X, Kar R, Gluhak-Heinrich J, et al (2010). Glucocorticoidinduced autophagy in osteocytes. J Bone Miner Res, 25, 2479-88.
  42. Xing X, Zhang L, Wen X, et al (2014). PP242 suppresses cell proliferation, metastasis, and angiogenesis of gastric cancer through inhibition of the PI3K/AKT/mTOR pathway. Anticancer Drugs [Epub ahead of print].
  43. Yamamoto T, Nishiguchi M, Inoue N, et al (2002). Inhibition of murine osteosarcoma cell proliferation by glucocorticoid. Anticancer Res, 22, 4151-6.
  44. Yothaisong S, Dokduang H, Techasen A, et al (2013). Increased activation of PI3K/AKT signaling pathway is associated with cholangiocarcinoma metastasis and PI3K/mTOR inhibition presents a possible therapeutic strategy. Tumour Biol, 34, 3637-48.

Cited by

  1. Flavone inhibits migration through DLC1/RhoA pathway by decreasing ROS generation in breast cancer cells vol.52, pp.5, 2016,
  2. Alkaloids of fascaplysin are effective conventional chemotherapeutic drugs, inhibiting the proliferation of C6 glioma cells and causing their death in vitro vol.13, pp.2, 2016,
  3. Glucocorticoid resistance of migration and gene expression in a daughter MDA-MB-231 breast tumour cell line selected for high metastatic potential vol.7, pp.1, 2017,
  4. All-Trans Retinoic Acid Enhances Matrix Metalloproteinase 2 Expression and Secretion in Human Myeloid Leukemia THP-1 Cells vol.2018, pp.2314-6141, 2018,
  5. Glucocorticoid signaling regulates cell invasion and migration in the human first-trimester trophoblast cell line Sw.71 vol.80, pp.1, 2018,