Auriculasin induces LACTB expression to regulate colorectal cancer cell apoptosis, ferroptosis, invasion, and in vivo tumor growth

Abstract

Previous studies have found that auriculasin isolated from Flemingia philippinensis has a significant anticancer effect in colorectal cancer (CRC), but there are few studies on its mechanism. Treatment of CRC cells with auriculasin showed that auriculasin promoted LACTB expression in a dose-dependent manner, thereby enhancing reactive oxygen species (ROS) production and inhibiting cell viability. Auriculasin significantly enhanced CRC cell apoptosis and caspase-3/8/9 activities, and overexpression of LACTB also increased the caspase activities, but LACTB siRNA or N-acetyl-L-cysteine (NAC) significantly reduced the pro-apoptotic effects of auriculasin and LACTB. Auriculasin or LACTB overexpression significantly inhibited cell invasion, reducing the expression and secretion of matrix metalloproteinase (MMP)-2/9, while LACTB siRNA or NAC restored cell invasion levels. Auriculasin also significantly increased the levels of Fe²⁺ and malondialdehyde (MDA), and inhibited the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), but these effects were suppressed by LACTB siRNA; meanwhile, the inhibitory effects of auriculasin, LACTB overexpression and ferroptosis inducer erastin on cell viability could be blocked by the ferroptosis inhibitor ferrostatin-1 or LACTB siRNA, indicating that auriculasin induced ferroptosis through LACTB. Further xenograft mouse model (the most commonly used animal model for tumor research) also showed that auriculasin suppressed tumor growth, increased Fe²⁺ and MDA levels, and inhibited GPX4 and SLC7A11 expression, while LACTB knockdown restored tumor growth by reducing ferroptosis. Therefore, auriculasin enhances ROS production by inducing LACTB expression, thereby increasing apoptosis and ferroptosis, inhibiting cell invasion, and ultimately reducing tumor growth.