CD133+HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway

S. Ma, Kin Wah Lee, B. J. Zheng, K. W. Chan, X. Y. Guan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

608 Citations (Scopus)

Abstract

The recent discovery of cancer stem cells (CSCs) has played a pivotal role in changing our view of carcinogenesis and chemotherapy. Based on this concept, CSCs are responsible for the formation and growth of neoplastic tissue and are naturally resistant to chemotherapy, explaining why traditional chemotherapies can initially shrink a tumor but fails to eradicate it in full, allowing eventual recurrence. Recently, we identified a CSC population in hepatocellular carcinoma (HCC) characterized by their CD133 phenotype. However, the molecular mechanism by which it escapes conventional therapies remains unknown. Here, we examined the sensitivity of these cells to chemotherapeutic agents (doxorubicin and fluorouracil) and the possible mechanistic pathway by which resistance may be regulated. Purified CD133+HCC cells isolated from human HCC cell line and xenograft mouse models survived chemotherapy in increased proportions relative to most tumor cells which lack the CD133 phenotype; the underlying mechanism of which required the preferential expression of survival proteins involved in the Akt/PKB and Bcl-2 pathway. Treatment of CD133+HCC cells with an AKT1 inhibitor, specific to the Akt/PKB pathway, significantly reduced the expression of the survival proteins that was normally expressed endogenously. In addition, treatment of unsorted HCC cells with both anticancer drugs in vitro significantly enriched the CD133+subpopulation. In conclusion, our results show that CD133+HCC cells contribute to chemoresistance through preferential activation of Akt/PKB and Bcl-2 cell survival response. Targeting of this specific survival signaling pathway in CD133+HCC CSCs may provide a novel therapeutic model for the disease.
Original languageEnglish
Pages (from-to)1749-1758
Number of pages10
JournalOncogene
Volume27
Issue number12
DOIs
Publication statusPublished - 13 Mar 2008
Externally publishedYes

Keywords

  • Cancer stem cells
  • CD133
  • Chemoresistance
  • HCC
  • Survival

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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