Curcumin effectively inhibits oncogenic NF-κB 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-kB signaling. Methods We evaluated the CSCs-depleting potential of NF-kB 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-kB 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-kB 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-kB-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-kB inhibition. Conclusions These results demonstrate that blocking NF-kB can specifically target CSC populations and suggest a potential for combined inhibition of NF-kB and HDAC signaling for treatment of liver cancer patients with poor prognosis.

Curcumin induces apoptotic cell death and protective autophagy in human gastric cancer cells

“…As a natural compound, it has been proven to be effective with minimal toxicity, which selectively acts on cancer cells over normal cells (5,6). Hitherto, curcumin and its analog have been reported to play an anticancer role in several tumor models, including glioblastoma (7), liver (8), colorectal (9), lung (10), ovarian (11), breast (12) and oral (13) cancer. The underlying mechanisms have been demonstrated to be associated with the inhibition of proliferation, angiogenesis, invasion and metastasis of cancer cells, or apoptosis induction by curcumin (14)(15)(16).…”

Curcumin Analogue CA15 Exhibits Anticancer Effects on HEp-2 Cells via Targeting NF-κB

“…As a natural compound isolated from plants, curcumin has a low toxicity but a remarkable anticancer effect on various malignancies such as lung cancer, liver cancer, and colon cancer [18–20]. Apart from that, curcumin is considered to be a repressor of LSCC growth via topical application [9].…”

Nutritional Epigenetics and the Prevention of Hepatocellular Carcinoma with Bioactive Food Constituents

“…Also, a similar HDAC-inhibitory effect is exhibited by other bioactive food constituents, e.g., curcumin, (185) and allyl isothiocyanate (186). Recently, Maequardt et al (187) demonstrated that curcumin treatment induced cell death in HCC, especially in cells with the aggressive progenitor phenotype, and this effect may be attributed to HDAC inhibition.…”