Tylophora yunnanensis extract inhibits cholesterol biosynthesis to suppress triple negative breast cancer
Ethnopharmacological relevance Female breast cancer ranks second in incidence rate and fourth in mortality globally. Tylophora yunnanensis Schlechter (Asclepiadaceae) is frequently used in folk medicine to treat irregular menses, falls caused injuries, rheumatoid arthritis, hepatitis, gastric ulcers, and gynecological tumors. Aims of the study To explore the molecular mechanism of T. yunnanensis against breast cancer. Materials and methods Numerous experiments were implemented for detection of cell proliferation, death, toxicity, MMP, cycle, apoptosis, DNA damage, and cholesterol levels. Transcriptomic analysis, proteomic analysis, exogenous cholesterol antagonism, gene overexpression and western blot were performed to explore the mechanism of action. A tumor-bearing animal model was utilized. The chemical composition of T. yunnanensis extract (TYE) was analyzed using LC-MS/MS. Results TYE repressed the proliferation of BT549 and 4T1 cells, with IC 50 values of 4.88, 2.98 μg/mL for 24 h and 4.70, 1.87 μg/mL for 48 h, respectively. Cell cycle arrest was also induced. The multi-omics analysis displayed that TYE suppressed cholesterol biosynthesis and interfered with DNA damage repair in TNBC cells. Exogenous cholesterol reversed these effects, counteracted the elevated intracellular TC, FC, γ-H2AX, and tail moment. TYE downregulated the expression of SQLE, MVK, FDPS, TM7SF2, and DHCR24 proteins, which was offset by addition of cholesterol. Overexpression of SQLE reduced the inhibition effects of TYE on cell viability but was not responsible for the expression inhibition of MVK, FDPS and DHCR24 proteins. TYE decreased the tumor growth, serum TC and TG, and in situ expression of ki67 and SQLE in tumor-bearing mice and had no acute toxicity to mice. No chemical components of TYE were identified. Conclusion TYE inhibits SQLE transcription to decrease its protein expression, reduces cholesterol biosynthesis and accumulation, impedes DNA damage repair, leading to cell cycle arrest, and thus elicits cell death, followed by obstruction of breast cancer progression. T. yunnanensis may be a novel anti-breast cancer agent owing to its inhibitory effects on cholesterol biosynthesis.
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