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Evidence That Calebin A, a Component of Curcuma Longa Suppresses NF-B Mediated Proliferation, Invasion and Metastasis of Human Colorectal Cancer Induced by TNF-β (Lymphotoxin)

1
Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D−80336 Munich, Germany
2
Biomedical Center, Core facility animal models, Ludwig-Maximilian-University Munich, D-82152 Martinsried, Germany
3
Institute of Pathology, School of Medicine, Technical University of Munich, D-81675 Munich, Germany
4
Cancer Biology Laboratory & DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India
5
Inflammation Research Center, San Diego, CA 92126, USA
*
Author to whom correspondence should be addressed.
Nutrients 2019, 11(12), 2904; https://doi.org/10.3390/nu11122904
Received: 24 October 2019 / Revised: 24 November 2019 / Accepted: 28 November 2019 / Published: 1 December 2019
Objective: Natural polyphenol Calebin A has been recently discovered as a novel derivate from turmeric with anti-cancer potential. Pro-inflammatory cytokine TNF-β (lymphotoxin α) is a stimulant for cancer cell malignity via activation of NF-B pathway, also in colorectal cancer (CRC). Here, we investigated the potential of Calebin A to suppress TNF-β-induced NF-B signalling in CRC. Materials and Methods: Three distinct CRC cell lines (HCT116, RKO, SW480) were treated in monolayer or 3-dimensional alginate culture with TNF-β, Calebin A, curcumin, BMS-345541, dithiothreitol (DTT) or antisense oligonucleotides-(ASO) against NF-B. Results: Calebin A suppressed dose-dependent TNF-β-induced CRC cell vitality and proliferation in monolayer culture. Further, in alginate culture, Calebin A significantly suppressed TNF-β-enhanced colonosphere development, as well as invasion and colony formation of all three CRC cell lines investigated. Calebin A specifically blocked TNF-β-induced activation and nuclear translocation of p65-NF-B, similar to curcumin (natural NF-B inhibitor), BMS-345541 (specific IKK inhibitor) and ASO-NF-B. Moreover, Immunofluorescence and Immunoblotting showed that Calebin A, similar to curcumin or BMS-345541 suppressed TNF-β-induced activation and nuclear translocation of p65-NF-B and the transcription of NF-B-promoted biomarkers associated with proliferation, migration and apoptosis, in a dose- and time-dependent manner. Those findings were potentiated by the specific treatment of extracted nuclei with DTT, which abrogated Calebin A-mediated nuclear p65-NF-B-inhibition and restored p65-NF-B-activity in the nucleus. Conclusion: Overall, these results demonstrate, for the first time, that multitargeted Calebin A has an anti-cancer capability on TNF-β-induced malignities through inhibitory targeting of NF-B activation in the cytoplasm, as well as by suppressing the binding of p65-NF-B to DNA.
Keywords: Calebin A; Curcumin; Colorectal Cancer; TNF-β (Lymphotoxin), NF-B; Metastasis Calebin A; Curcumin; Colorectal Cancer; TNF-β (Lymphotoxin), NF-B; Metastasis
MDPI and ACS Style

Buhrmann, C.; Popper, B.; Kunnumakkara, A.B.; Aggarwal, B.B.; Shakibaei, M. Evidence That Calebin A, a Component of Curcuma Longa Suppresses NF-B Mediated Proliferation, Invasion and Metastasis of Human Colorectal Cancer Induced by TNF-β (Lymphotoxin). Nutrients 2019, 11, 2904.

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