Norisoboldine suppresses epithelial-mesenchymal transition in colorectal cancer by simultaneously inhibiting the CXCR4/CXCR7 chemokine receptors and the JAK/STAT3 signaling pathway.

OBJECTIVES: Norisoboldine (NOR), an isoquinoline alkaloid from Radix Linderae, has known anti-inflammatory properties, but its role in colorectal cancer remains unclear.

METHODS: HCT-15, SW480, and HT-29 cells were treated with NOR and assessed via MTT, Western blotting, zymography, wound-healing, invasion assays, and STAT3 loss/gain-of-function experiments. Molecular docking explored NOR-STAT3 interaction.

KEY FINDINGS: NOR showed limited cytotoxicity at the concentrations used for mechanistic experiments. NOR decreased the expression of mesenchymal and metastasis-associated proteins, including Vimentin, Twist, Snail, CXCR4, CXCR7, MMP-2, and MMP-9, while increasing E-cadherin and Occludin levels. NOR also reduced gelatinolytic activity and attenuated CXCL12-enhanced migration and invasion. In parallel, NOR decreased phosphorylation of STAT3 and its upstream kinases JAK1, JAK2, and Src, and reduced nuclear accumulation of STAT3. STAT3 knockdown lowered CXCR4, CXCR7, and Snail expression, whereas STAT3 overexpression produced the opposite pattern; NOR partly reversed these changes. Docking analysis suggested that NOR may interact with the SH2 domain of STAT3, although this requires biochemical validation.

CONCLUSION: NOR attenuates epithelial-mesenchymal transition and invasive phenotypes in colorectal cancer cells via JAK/STAT3 suppression, positioning it as a candidate anti-metastatic modulator. Further in vivo and target-engagement studies are warranted.