CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway
- 24 September 2007
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 27 (12), 1749-1758
- https://doi.org/10.1038/sj.onc.1210811
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.Keywords
This publication has 27 references indexed in Scilit:
- CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicityInternational Journal of Cancer, 2007
- Identification and expansion of human colon-cancer-initiating cellsNature, 2006
- A human colon cancer cell capable of initiating tumour growth in immunodeficient miceNature, 2006
- Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cellsBiochemical and Biophysical Research Communications, 2006
- Promoting apoptosis as a strategy for cancer drug discoveryNature Reviews Cancer, 2005
- Tumour stem cells and drug resistanceNature Reviews Cancer, 2005
- Prospective identification of tumorigenic breast cancer cellsProceedings of the National Academy of Sciences, 2003
- The Hallmarks of CancerCell, 2000
- Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death MachineryCell, 1997
- Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cellNature Medicine, 1997