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Tumor Biology

, Volume 37, Issue 6, pp 8047–8055 | Cite as

MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK

  • Beibei Zhai
  • Xiaofeng Zhang
  • Bin Sun
  • Lu Cao
  • Linlin Zhao
  • Jun Li
  • Naijian Ge
  • Lei Chen
  • Haihua Qian
  • Zhengfeng Yin
Original Article

Abstract

Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib.

Keywords

Hepatocellular carcinoma Liver cancer stem cells Sorafenib MK2206 

Notes

Acknowledgments

This study was supported by grants from the National Nature Science Foundation of China (Nos. 81201721, 81172207, and 81272669) and the China National Key Projects for Infectious Disease (No. 2012ZX10002012-10).

Compliance with ethical standards

Conflicts of interest

None.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina
  2. 2.Department of Radioactive Intervention, Eastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghaiChina

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