Phosphatidylinositol 3-Kinase and Protein Kinase C as Molecular Determinants of Chemoresistance in Breast Cancer
Abstract
Using an isogenic model of breast cancer resistance we have previously demonstrated that generation ceramide is inversely correlated with apoptosis in chemoresistant MCF-7 cells. Additionally, we have shown that the NF-kB pathway is an important determinant for MCF-7 cell survival, and that expression of the NF-kB inhibitory protein, IkB, was diminished in chemoresistant cells. To elucidate the connections between these two factors and cell survival, we used a super. repressive form of lkB. We found that lkB-SR decreased survival in both chemosensitive and chemoresistant MCF-7 cells and enhanced TNFalpha-induced cell death. Overexpression of the p65 and p50 NF-kB subunits did not significantly alter viability, either alone or with cytotoxic treatment, suggesting that control of NF-kB signaling by lkB is a main mechanism of pro-survival NF-kB signaling. Interestingly, ceramide treatment inhibited NF-kB activity, through preventing the degradation of lkB, an effect that may contribute to the cytotoxicity of ceramide. Finally, we show that the cytotoxic effect of exogenous ceramide treatment is selective for cancer cells as treatment of non-transformed breast epithelial cells did not significantly decrease viability. This work provide evidence for the importance of the NF-kB transcriptional pathway in breast cancer cell survival, and suggests that targeting NF-kB signaling (through ceramide treatment) is a potential therapeutic treatment in breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA431891
Entities
People
- Amanda Parker
- Barbara Beckman
- Matthew E. Burow
Organizations
- Tulane University of Louisiana