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Brockmueller, Aranka; Girisa, Sosmitha; Motallebi, Mahzad; Kunnumakkara, Ajaikumar B.; Shakibaei, Mehdi (2023): Calebin A targets the HIF-1α/NF-κB pathway to suppress colorectal cancer cell migration. Frontiers in Pharmacology, 14: 1203436. ISSN 1663-9812

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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.

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