Evidence That Tumor Microenvironment Initiates Epithelial-To-Mesenchymal Transition and Calebin A can Suppress it in Colorectal Cancer Cells

Constanze Buhrmann; Aranka Brockmueller; Choudhary Harsha; Ajaikumar B Kunnumakkara; Peter Kubatka; Bharat B Aggarwal; Mehdi Shakibaei

doi:10.3389/fphar.2021.699842

Evidence That Tumor Microenvironment Initiates Epithelial-To-Mesenchymal Transition and Calebin A can Suppress it in Colorectal Cancer Cells

Front Pharmacol. 2021 Jul 2:12:699842. doi: 10.3389/fphar.2021.699842. eCollection 2021.

Authors

Constanze Buhrmann^{1

2}, Aranka Brockmueller¹, Choudhary Harsha³, Ajaikumar B Kunnumakkara³, Peter Kubatka⁴, Bharat B Aggarwal⁵, Mehdi Shakibaei¹

Affiliations

¹ Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilian-University Munich, Munich, Germany.
² Faculty of Medicine, Institute of Anatomy and Cell Biology, University of Augsburg, Augsburg, Germany.
³ Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, India.
⁴ Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia.
⁵ Inflammation Research Center, San Diego, CA, United States.

Abstract

Background: Tumor microenvironment (TME) has a pivotal impact on tumor progression, and epithelial-mesenchymal transition (EMT) is an extremely crucial initial event in the metastatic process in colorectal cancer (CRC) that is not yet fully understood. Calebin A (an ingredient in Curcuma longa) has been shown to repress CRC tumor growth. However, whether Calebin A is able to abrogate TME-induced EMT in CRC was investigated based on the underlying pathways. Methods: CRC cell lines (HCT116, RKO) were exposed with Calebin A and/or a FAK inhibitor, cytochalasin D (CD) to investigate the action of Calebin A in TME-induced EMT-related tumor progression. Results: TME induced viability, proliferation, and increased invasiveness in 3D-alginate CRC cultures. In addition, TME stimulated stabilization of the master EMT-related transcription factor (Slug), which was accompanied by changes in the expression patterns of EMT-associated biomarkers. Moreover, TME resulted in stimulation of NF-κB, TGF-β1, and FAK signaling pathways. However, these effects were dramatically reduced by Calebin A, comparable to FAK inhibitor or CD. Finally, TME induced a functional association between NF-κB and Slug, suggesting that a synergistic interaction between the two transcription factors is required for initiation of EMT and tumor cell invasion, whereas Calebin A strongly inhibited this binding and subsequent CRC cell migration. Conclusion: We propose for the first time that Calebin A modulates TME-induced EMT in CRC cells, at least partially through the NF-κB/Slug axis, TGF-β1, and FAK signaling. Thus, Calebin A appears to be a potential agent for the prevention and management of CRC.

Keywords: Calebin A; EMT; NF- kappa B; TGF - β1; colorecal cancer; focal adhesion kinase; slug; tumor microenvironment.