Page 54 - ebook HCC

52 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 53
FEBRUARY 13 - 16, 2014

SPECIFIC TARGETING OF STEM-LIKE CELLS IN
LIVER CANCER BY NF-KB MEDIATED INHIBITON
OF HISTONE DEACETYLASES

Jens U. Marquardt , Luis Gomez-Quirez , Lucrecia O. Arreguin Camacho , Frederico Specific inhibition of NF-kB signaling by SN50 and siRNA led to general suppression
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Pinna , Yun-Han Lee , Jesper B. Andersen , Kai Breuhahn , Peter R. Galle , Valentina of cell growth accompanied by a drastic reduction in the size of SP fraction confirming
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M. Factor , Snorri S. Thorgeirsson 2 that the response to curcumin was dependent on effective disruption of the NF-kB
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1 University of Mainz, Department of Medicine I, Mainz, Germany, Laboratory of pathway. Mechanistically, CSC-depleting activity was exerted by NF-kB mediated histone
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Experimental Carcinogenesis, CCR/NCI/NIH, Bethesda, United States, Universidad deacetylase (HDAC) inhibition leading to down-regulation of c-MYC and other key
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Autónoma Metropolitana-Iztapalapa, Departamento de Ciencias de la Salud, Mexico, oncogenic targets. Co-administration of a class I and II HDAC inhibitor sensitized resistant
Mexico, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany cells to curcumin treatment. Further, integration of a predictive signature with our HCC
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database indicated that with patients with poor prognosis and progenitor features are most
Corresponding author’s e-mail: marquarj@uni-mainz.de likely to benefit from NF-kB inhibition.
BASIC SPEAKERS ABSTRACTS Introduction: The cancer stem cells (CSCs) hypothesis possesses important therapeutic target CSC populations, providing an important step towards CSC-directed HCC therapy. BASIC SPEAKERS ABSTRACTS
Conclusions: Together, these data demonstrate that NF-kB inhibtion can specifically
implications for multi-resistant cancers such as hepatocellular carcinoma. We have
Future investigations will determine the potential of combined targeting NF-kB signaling as
well as HDAC for the treatment of liver cancer patients with poor prognosis.
recently reported that activation of NF-kB signaling is consistently observed in stem-like
cells in human liver cancer.
Aims: Based on these data, we hypothesized that NF-kB may be a specific therapeutic
target against hepatic CSCs.
Methodology: Inhibition of NF-kB signaling was performed using curcumin, an effective IKK
inhibitor, siRNA against p65 and by the specific inhibitory peptide SN50. Anti-proliferative
and pro-apoptotic capacity of the drug was evaluated in different liver cancer cells. The
effect on CSC was assessed by the Side Population (SP) approach, and expression levels
of selected targets determined by RT-qPCR, gene expression microarray, EMSA, and
Western blotting.
Results: Curcumin treatment caused anti-proliferative and pro-apoptotic responses
directly related to the extent of NF-kB inhibition. In curcumin-sensitive cell lines, the
treatment led to a selective depletion of CSC reflected by a significant reduction in the SP
population, sphere formation and tumorigenicity as well as subsequent down-regulation of
selected CSC markers, such as CD133, EpCAM, NANOG and c-Kit. In contrast, curcumin-
resistant cells exhibited a paradoxical increase in proliferation and activation of the CSC
markers in response to the treatment.