Zerumbone modulates CD1d expression and lipid antigen presentation pathway in breast cancer cells

- CD1d expression increases with advanced stages of breast cancer cells.
- Zerumbone inhibited CD1d antigen presentation pathway including CD1d expression.
- α-GalCer enhanced CD1d as well as survival and proliferation of breast cancer cells.
- CD1d-mediated cell survival was likely through ERK1/2 and Akt pathways.
- CD1d blockade led apoptosis and cell cycle arrest; further enhanced by zerumbone.

Natural Killer T (NKT) cells based cancer immunotherapy is an evolving area of cancer therapy, but tumors escape from this treatment modality by altering CD1d expression and its antigen presentation pathway. Here, we have studied the relation of CD1d expression in various breast cancer cell lines to their viability and progression. We observed a novel phenomenon that CD1d expression level increases with the progressive stage of the cancer. A small molecule, zerumbone (ZER) caused down-regulation of CD1d that was accompanied by breast cancer cell growth in vitro. The growth inhibitory effect of ZER against breast cancer cells was augmented by treatment with anti-CD1d mAb. This effect was mediated by G1-phase cell cycle arrest and apoptosis induction coupled with an increase in mitochondrial membrane depolarization. CD1d expression and cell proliferation were inhibited by both CD1d siRNA and ZER. The α-galactosylceramide, a ligand for CD1d, showed increased CD1d expression as well as cell proliferation which was opposite to the effects of ZER. This study shows that, CD1d overexpression is associated with the progressive stages of breast cancer and ZER could be an adjuvant to potentiate cancer immunotherapy.

153