Curcumin effectively inhibits oncogenic NF-kB signaling and restrains stemness features in liver cancer

Jens U Marquardt; Luis Gomez-Quiroz; Lucrecia O Arreguin Camacho; Federico Pinna; Yun-Han Lee; Mitsuteru Kitade; Mayrel Palestino Domínguez; Darko Castven; Kai Breuhahn; Elizabeth A Conner; Peter R Galle; Jesper Bøje Andersen; Valentina M Factor; Snorri S Thorgeirsson

doi:10.1016/j.jhep.2015.04.018

Curcumin effectively inhibits oncogenic NF-kB signaling and restrains stemness features in liver cancer

Jens U Marquardt, Luis Gomez-Quiroz, Lucrecia O Arreguin Camacho, Federico Pinna, Yun-Han Lee, Mitsuteru Kitade, Mayrel Palestino Domínguez, Darko Castven, Kai Breuhahn, Elizabeth A Conner, Peter R Galle, Jesper Bøje Andersen, Valentina M Factor, Snorri S Thorgeirsson

132 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Hepatology
DOIs	https://doi.org/10.1016/j.jhep.2015.04.018
Publication status	Published - 1 Sept 2015

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Marquardt, J. U., Gomez-Quiroz, L., Arreguin Camacho, L. O., Pinna, F., Lee, Y.-H., Kitade, M., Domínguez, M. P., Castven, D., Breuhahn, K., Conner, E. A., Galle, P. R., Andersen, J. B., Factor, V. M., & Thorgeirsson, S. S. (2015). Curcumin effectively inhibits oncogenic NF-kB signaling and restrains stemness features in liver cancer. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2015.04.018

Marquardt, JU, Gomez-Quiroz, L, Arreguin Camacho, LO, Pinna, F, Lee, Y-H, Kitade, M, Domínguez, MP, Castven, D, Breuhahn, K, Conner, EA, Galle, PR, Andersen, JB, Factor, VM & Thorgeirsson, SS 2015, 'Curcumin effectively inhibits oncogenic NF-kB signaling and restrains stemness features in liver cancer', Journal of Hepatology. https://doi.org/10.1016/j.jhep.2015.04.018

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title = "Curcumin effectively inhibits oncogenic NF-kB signaling and restrains stemness features in liver cancer",

abstract = "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.",

author = "Marquardt, {Jens U} and Luis Gomez-Quiroz and {Arreguin Camacho}, {Lucrecia O} and Federico Pinna and Yun-Han Lee and Mitsuteru Kitade and Dom{\'i}nguez, {Mayrel Palestino} and Darko Castven and Kai Breuhahn and Conner, {Elizabeth A} and Galle, {Peter R} and Andersen, {Jesper B{\o}je} and Factor, {Valentina M} and Thorgeirsson, {Snorri S}",

note = "Copyright {\textcopyright} 2015. Published by Elsevier B.V.",

year = "2015",

month = sep,

day = "1",

doi = "10.1016/j.jhep.2015.04.018",

language = "English",

journal = "Journal of Hepatology",

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TY - JOUR

T1 - Curcumin effectively inhibits oncogenic NF-kB signaling and restrains stemness features in liver cancer

AU - Marquardt, Jens U

AU - Gomez-Quiroz, Luis

AU - Arreguin Camacho, Lucrecia O

AU - Pinna, Federico

AU - Lee, Yun-Han

AU - Kitade, Mitsuteru

AU - Domínguez, Mayrel Palestino

AU - Castven, Darko

AU - Breuhahn, Kai

AU - Conner, Elizabeth A

AU - Galle, Peter R

AU - Andersen, Jesper Bøje

AU - Factor, Valentina M

AU - Thorgeirsson, Snorri S

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.jhep.2015.04.018

DO - 10.1016/j.jhep.2015.04.018

M3 - Journal article

C2 - 25937435

SN - 0169-5185

SN - 1600-0641

JO - Journal of Hepatology

JF - Journal of Hepatology

ER -

Curcumin effectively inhibits oncogenic NF-kB signaling and restrains stemness features in liver cancer

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