A Sterol from Soft Coral Induces Apoptosis and Autophagy in MCF-7 Breast Cancer Cells

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that plays a key role in regulating cellular metabolism, and is a therapeutic target for cancer therapy. To search for potential PPAR gamma activators, a compound library comprising 11 marine compounds was examined. Among them, a sterol, 3 beta,11-dihydroxy-9,11-secogorgost-5-en-9-one (compound 1), showed the highest PPAR gamma activity with an IC(50 )value of 8.3 mu M for inhibiting human breast adenocarcinoma cell (MCF-7) growth. Western blotting experiments showed that compound 1 induces caspase activation and PARP cleavage. In addition, compound 1 modulated the expression of various PPAR gamma-regulated downstream biomarkers including cyclin D1, cyclin-dependent kinase (CDK)6, B-cell lymphoma 2 (Bcl-2), p38, and extracellular-signal-regulated kinase (ERK). Moreover, compound 1 increased reactive oxygen species (ROS) generation, upregulated the phosphorylation and expression of H2AX, and induced autophagy. Interestingly, pre-treatment with the autophagy inhibitor 3-methyladenine rescued cells from compound 1-induced growth inhibition, which indicates that the cytotoxic effect of compound 1 is, in part, attributable to its ability to induce autophagy. In conclusion, these findings suggest the translational potential of compound 1 in breast cancer therapy.