Skullcapflavone II Suppresses Colorectal Cancer by Inhibiting the HIF-1α-Glycolysis Pathway

Our aim is to explore Skullcapflavone II (SFII) function in colorectal Cancer and delineate its relevant mechanisms. Malignant behaviors of HCT-116 and SW480 cells were assessed using colony formation, 5-ethynyl-2'-deoxyuridine staining, Annexin V/propidium iodide double staining, scratch and transwell assays. Changes in glycolysis were assessed by seahorse assay and western blot. The potential mechanism by which SFII inhibited the expression of hypoxia-inducible transcription factor-1alpha (HIF-1α) was explored in vitro by molecular docking, surface plasmon resonance, quantitative reverse transcription polymerase chain reaction, western blot, immunofluorescence, cycloheximide chase assay, ubiquitination assay, and some rescue experiments. Besides, a xenograft model was performed to verify SFII function on colorectal Cancer. We found that SFII inhibited the malignant behavior and glycolysis of colorectal Cancer cells. Furthermore, SFII inhibited HIF-1α protein level in colorectal Cancer cells via enhancing its ubiquitination. Moreover, HIF-1α overexpression attenuated SFII effect on the malignant behavior and glycolysis in colorectal Cancer cells. In vivo, SFII inhibited tumorigenesis through repressing the HIF-1α-glycolysis pathway in BALB/c nude mice. SFII could suppress proliferation, migration, and invasion in colorectal Cancer through inhibiting the HIF-1α-glycolysis pathway.

HIF‐1α; Skullcapflavone II; colorectal cancer; glycolysis; invasion; migration; proliferation.