Background & Aims
The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant
cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently
activated in liver CSCs is NF-κB signaling.
Methods
We evaluated the CSCs-depleting potential of NF-κB inhibition in liver cancer achieved
by the IKK inhibitor curcumin, RNAi and specific peptide SN50. The effects on CSCs
were assessed by analysis of side population (SP), sphere formation and tumorigenicity.
Molecular changes were determined by RT-qPCR, global gene expression microarray, EMSA,
and Western blotting.
Results
HCC cell lines exposed to curcumin exhibited differential responses to curcumin and
were classified as sensitive and resistant. In sensitive lines, curcumin-mediated
induction of cell death was directly related to the extent of NF-κB inhibition. The
treatment also led to a selective CSC-depletion as evidenced by a reduced SP size,
decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity.
Similarly, NF-κB inhibition by SN50 and siRNA against p65 suppressed tumor cell growth.
In contrast, curcumin-resistant cells displayed a paradoxical increase in proliferation
and expression of CSC markers. Mechanistically, an important component of the CSC-depleting
activity of curcumin could be attributed to a NF-κB-mediated HDAC inhibition. Co-administration
of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin.
Further, integration of a predictive signature of curcumin sensitivity with human
HCC database indicated that HCCs with poor prognosis and progenitor features are most
likely to benefit from NF-κB inhibition.
Conclusions
These results demonstrate that blocking NF-κB can specifically target CSC populations
and suggest a potential for combined inhibition of NF-κB and HDAC signaling for treatment
of liver cancer patients with poor prognosis.
Keywords
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Article info
Publication history
Published online: April 30, 2015
Accepted:
April 14,
2015
Received in revised form:
March 20,
2015
Received:
September 30,
2014
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
