背景：缺氧诱导因子-1α（HIF-1α）是主要的与肿瘤相关的转录因子之一，能够调节许多肿瘤特性，如肿瘤细胞的代谢、存活、增殖、血管生成和转移。Calebin A（CA）是从姜黄中提取的一种化合物，通过调节NF-κB通路来发挥其抗癌活性。然而，它对结直肠癌（CRC）细胞迁移中的HIF-1α的影响尚不清楚。方法：使用3D海藻酸钠和单层多细胞TME（成纤维细胞/T淋巴细胞）培养的人CRC细胞（HCT-116），暴露于CA或HIF-1α抑制剂，探究CA对TME诱导的炎症、迁移和肿瘤恶性程度的疗效。结果：CA显著抑制了TME促进的HCT-116细胞增殖和迁移，与HIF-1α抑制剂类似。胶块形成、甲苯胺蓝染色和免疫标记显示，CA通过部分抑制HIF-1α来抑制HCT-116细胞的迁移，HIF-1α对CRC细胞的存活至关重要，这些观察结果通过电镜得到证实。此外，Western blot分析证实，CA抑制了TME诱导的HIF-1α和转移因子生物标志物（如NF-κB、β1整合素和VEGF）的表达，并促进了凋亡（caspase-3），这与HIF-1α抑制剂相似。最后，TME引起了HIF-1α和NF-κB之间有意的配对，推测两个与肿瘤相关的转录因子之间的协同作用对CRC细胞的恶性和迁移至关重要，并且CA以串联方式沉默了这些因子。结论：这些结果揭示了CA信号在CRC细胞迁移中的一种新的调控模式，部分通过HIF-1α/NF-κB，这对癌症治疗可能具有相关的意义。版权所有 © 2023 Brockmueller, Girisa, Motallebi, Kunnumakkara和Shakibaei。

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.Copyright © 2023 Brockmueller, Girisa, Motallebi, Kunnumakkara and Shakibaei.