Inhibition of p53 sensitizes MCF-7 cells to ceramide treatment.

Ceramide signaling plays an important role in tumor progression and development of chemoresistance, and ceramide-based therapies are proposed as potential therapeutic tools for the treatment of breast cancer. We investigated the effect of exogenous ceramide on the cell cycle progression of MCF-7 breast cancer cells. Ceramide induced a selective arrest of MCF-7 cells in the G1-phase, which was associated with a decreased expression of cyclins D and E and increased expression of p53 and p21. Interestingly, inhibition of p53 using pifithrin alpha or RNAi sensitized MCF-7 cells to ceramide-induced cell death. DNA content analysis suggested that sensitization of cells was due to an increased induction of apoptosis in MCF-7 cells. The increased sensitivity to ceramide, in the context of p53 inhibition, may be due to decreased expression of p21, as siRNA targeted to p21 also sensitized MCF-7 cells to ceramide-induced death. These data demonstrate that in tumors with inactivating mutations of p53, ceramide-based therapies might provide a novel and effective treatment option.