Over-Expression of Beclin-1 Facilitates Acquired Resistance to Histone Deacetylase Inhibitor-Induced Apoptosis

  • Wang, Shi-Miao (School of Life Science and Biotechnology, Dalian University of Technology) ;
  • Li, Xiao-Hui (School of Life Science and Biotechnology, Dalian University of Technology) ;
  • Xiu, Zhi-Long (School of Life Science and Biotechnology, Dalian University of Technology)
  • Published : 2014.10.11


Apoptotic cell death plays a predominant role in histone deacetylase (HDAC) inhibitor-induced cytotoxicity. Nuclear morphological changes and activation of apoptotic executors are involved in CTS203-induced cell death. However, emerging issues of HDAC inhibitor-resistance have been observed in patients. Herein, MCF-7 cells were continuously exposed to CTS203 until the derived cells could proliferate normally in its presence. The newly obtained CTS203-resistant cells were nominated as MCF-7/203R. Compared to MCF-7 original cells, the MCF-7/203R cells were less sensitive to CTS203-induced apoptosis, with a minimal 6-fold higher $IC_{50}$ value. In contrast, the expression of Beclin-1 was dramatically up-regulated, positively correlated to the acquisition of CTS203-resistance. Our results revealed the participation of autophagy in acquired HDAC inhibitor-resistance and further identified Beclin-1 as a promising target for anti-drug resistance.


  1. Chen YT, Feng B, Chen LB (2012). Update of research on drug resistance in small cell lung cancer chemotherapy. Asian Pac J Cancer Prev, 13, 3577-81.
  2. Abedin MJ, Wang D, McDonnell MA, et al (2007). Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ, 14, 500-10.
  3. Apel A, Herr I, Schwarz H, et al (2008). Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res, 68, 1485-94.
  4. Cai M, Hu Z, Liu J, et al (2014). Beclin 1 expression in ovarian tissues and its effects on ovarian cancer prognosis. Int J Mol Sci, 15, 5292-303.
  5. Carew JS, Nawrocki ST, Kahue CN, et al (2007). Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. Blood, 110, 313-22.
  6. Chen SY, Hu SS, Dong Q, et al (2013). Establishment of paclitaxel-resistant breast cancer cell line and nude mice models, and underlying multidrug resistance mechanisms in vitro and in vivo. Asian Pac J Cancer Prev, 14, 6135-40.
  7. Debatin KM (2004). Apoptosis pathways in cancer and cancer therapy. Cancer Immunol Immun, 53, 153-9.
  8. Eisenberg-Lerner A, Bialik S, Simon HU, et al (2009). Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ, 16, 966-75.
  9. Fantin VR, Richon VM (2007). Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications. Clin Cancer Res, 13, 7237-42.
  10. Gu W, Fang FF, Li B, et al (2012). Characterization and resistance mechanisms of A 5-fluorouracil-resistant hepatocellular carcinoma cell line. Asian Pac J Cancer Prev, 13, 4807-14.
  11. Hou W, Han J, Lu C, et al (2010). Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy, 6, 891-900.
  12. Jänicke RU (2009). MCF-7 breast carcinoma cells do not express caspase-3. Breast Cancer Res Tr, 117, 219-21.
  13. Li Z, Chen B, Wu Y, et al (2010). Genetic and epigenetic silencing of the beclin 1 gene in sporadic breast tumors. BMC Cancer, 10, 98.
  14. Juengel E, Makarevic J, Tsaur I, et al (2013). Resistance after chronic application of the HDAC-inhibitor valproic acid is associated with elevated Akt activation in renal cell carcinoma in vivo. PLoS One, 8, 53100.
  15. Kang R, Zeh HJ, Lotze MT, et al (2011). The beclin 1 network regulates autophagy and apoptosis. Cell Death Differ, 18, 571-80.
  16. Kim HJ, Bae SC (2011). Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anticancer drugs. Am J Transl Res, 3, 166-79.
  17. Sun Y, Liu J, Sui Y, et al (2011). Beclin-1 overexpression inhibits proliferation, invasion and migration of CaSki cervical cancer cells. Asian Pac J Cancer Prev, 12, 1269-73.
  18. Wang NN, Zhao LJ, Wu LN, et al (2013). Mechanistic analysis of taxol-induced multidrug resistance in an ovarian cancer cell line. Asian Pac J Cancer Prev, 14, 4983-8.
  19. Wang S, Li X, Wei Y, et al (2014). Discovery of potent HDAC inhibitors based on chlamydocin with inhibitory effects on cell migration. ChemMedChem, 9, 627-37.
  20. Xu CY, Jiang ZN, Zhou Y, et al (2013). Estrogen receptor $\alpha$ roles in breast cancer chemoresistance. Asian Pac J Cancer Prev, 14, 4049-52.
  21. Yang ZJ, Chee CE, Huang S, et al (2011). The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther, 10, 1533-41.
  22. Yokoyama T, Kondo Y, Bogler O, et al (2009). The Role of Autophagy and Apoptosis in the Drug Resistance of Cancer. Springer, New York.

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