Calebin A targets the HIF-1α/NF-κB pathway to suppress colorectal cancer cell migration

Aranka Brockmueller; Sosmitha Girisa; Mahzad Motallebi; Ajaikumar B Kunnumakkara; Mehdi Shakibaei

doi:10.3389/fphar.2023.1203436

Calebin A targets the HIF-1α/NF-κB pathway to suppress colorectal cancer cell migration

Front Pharmacol. 2023 Jul 31:14:1203436. doi: 10.3389/fphar.2023.1203436. eCollection 2023.

Authors

Aranka Brockmueller¹, Sosmitha Girisa², Mahzad Motallebi³, Ajaikumar B Kunnumakkara², Mehdi Shakibaei¹

Affiliations

¹ Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
² Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
³ Department of Biology, Yadegar-e-Imam Khomeini Shahr-e-Rey Branch, Islamic Azad University, Tehran, Iran.

Abstract

Background: Hypoxia-inducible factor-1α (HIF-1α) is one of the major tumor-associated transcription factors modulating numerous tumor properties such as tumor cell metabolism, survival, proliferation, angiogenesis, and metastasis. Calebin A (CA), a compound derived from turmeric, is known for its anti-cancer activity through modulation of the NF-κB pathway. However, its impact on HIF-1α in colorectal cancer (CRC) cell migration is unknown. Methods: Human CRC cells (HCT-116) in 3D alginate and monolayer multicellular TME (fibroblasts/T lymphocytes) were subjected to CA or the HIF-1α inhibitor to explore the efficacy of CA on TME-induced inflammation, migration, and tumor malignancy. Results: CA significantly inhibited TME-promoted proliferation and migration of HCT-116 cells, similar to the HIF-1α inhibitor. Colony formation, toluidine blue staining, and immunolabeling showed that CA inhibited the migration of HCT-116 cells partly by inhibiting HIF-1α, which is critical for CRC cell viability, and these observations were confirmed by electron microscopy. In addition, Western blot analysis confirmed that CA inhibited TME-initiated expression of HIF-1α and biomarkers of metastatic factors (such as NF-κB, β1-integrin, and VEGF), and promoted apoptosis (caspase-3), in a manner comparable to the HIF-1α inhibitor. Finally, TME induced a purposeful pairing between HIF-1α and NF-κB, suggesting that the synergistic interplay between the two tumor-associated transcription factors is essential for CRC cell malignancy and migration and that CA silences these factors in tandem. Conclusion: These results shed light on a novel regulatory modulation of CA signaling in CRC cell migration, partially via HIF-1α/NF-κB with potentially relevant implications for cancer therapy.

Keywords: 3D alginate; CRC migration; Calebin A; HIF-1α; NF-κB; apoptosis; neoangiogenesis; tumor microenvironment.