SBF-1 suppresses colorectal cancer cell growth via modulating cholesterol metabolic reprogramming

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide.
• There is a critical need for innovative therapeutic strategies against CRC.
• Targeting cellular metabolism presents a promising avenue for cancer treatment.

Purpose of the Study:

• To investigate the antitumor effects and mechanism of SBF-1, a compound from Ornithogalum caudatum Jacq.
• To elucidate how SBF-1 impacts cholesterol metabolism in colorectal cancer cells.
• To identify factors influencing cellular response to SBF-1.

Main Methods:

• Assessed SBF-1's impact on colorectal cancer cell viability.
• Quantified oxysterol-binding protein (OSBP) degradation and intracellular cholesterol levels.
• Performed comparative transcriptomic analysis to identify key determinants of SBF-1 sensitivity.
• Utilized gene knockdown and overexpression techniques to validate NPC2's role.

Main Results:

• SBF-1 significantly inhibited colorectal cancer cell viability in a dose-dependent manner.
• SBF-1 induced OSBP degradation, reduced intracellular cholesterol, and disrupted cholesterol homeostasis.
• NPC2 expression levels were identified as a critical determinant of SBF-1 sensitivity, with low NPC2 correlating to higher cytotoxicity.
• NPC2 knockdown sensitized resistant cells, while overexpression conferred resistance.

Conclusions:

• SBF-1 exhibits potent cytotoxic effects against colorectal cancer cells via OSBP degradation and cholesterol metabolic reprogramming.
• NPC2 acts as a key modulator of cellular susceptibility to SBF-1.
• These findings support the development of precision anticancer therapies targeting cholesterol metabolism in CRC.