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

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 þ 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 þ 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 þ subpopulation.In conclusion, our results show that CD133 þ 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 þ HCC CSCs may provide a novel therapeutic model for the disease.

Tunicamycin Potentiates Cisplatin Anticancer Efficacy through the DPAGT1/Akt/ABCG2 Pathway in Mouse Xenograft Models of Human Hepatocellular Carcinoma

“…5A-D). These data were consistent with previous reports indicating that the Akt/ABCG2 pathway contributes to chemotherapeutic resistance (13,30). As a tightly binding competitive inhibitor, tunicamycin inhibits NLG by inhibiting the DPAGT1-catalyzed transfer of GlcNAc-1-P from UDPGlcNAc to dolichyl-P.…”

Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations

“…Our work (10,11), along with the work of other research groups (8,9), suggests that human HCC is very likely to be also hierarchically organized and originates from a primitive stem/progenitor group of cells for which CD133 + precursors constitute one of the most immature stage. Results from our previous studies were mainly derived from experiments done on HCC cell lines or xenograft tumors where CD133 expression was as high as 48% to 65% (It was recently observed that HCC cell lines Huh7 and PLC8024 express varying levels of CD133 expression, ranging from 48% to 60% for PLC8024 and from 49% to 65% for Huh7.…”

“…CD133 expression is found to represent only a minority of the tumor cell population in human HCC specimens (8)(9)(10). In addition, CD133 + cells are also more resistant to conventional chemotherapeutic drugs such as doxorubicin and 5-fluorouracil, the underlying mechanism of which required the preferential activation of the Akt/protein kinase B and Bcl-2 survival pathways (11).…”

Expression of CD133+ cancer stem cells in childhood malignant melanoma and its correlation with metastasis

“…Therefore, the Akt pathway can be a target for novel antineoplastic therapies. 13 Furthermore, CD133 stem cell may pose as target for antibody-based therapies that would selectively eliminate these cells. 9 In conclusion, our study showed that CD133 þ cancer stem cell expression in childhood malignant melanoma might correlate with lymph node and/or visceral metastasis.…”