Phosphatidylinositol 3-Kinane and Protein Kinase C as Molecular Determinants of Chemoresistance in Breast Cancer
Abstract
The goal of this study is to investigate the role of Pl3K and PKC in chemoresistance in breast cancer and to use this information to identify novel therapeutic strategies aimed at counteracting or reversing drug resistance in breast cancer. We are using an isogenic model of breast cancer resistance with apoptosis-sensitive and apoptosis-resistant MCF-7 cells. Our preliminary data implicate the absence of PKC alpha, and a constitutive activation of the PKC alpha and Pl3K-Akt/NF-kB pathways as potential survival signals in our recently derived TN F-resistant MCF-7TN-R cells. Pharmacological inhibition of PKC and Pl3K led to a decrease in cell viability in both chemoresistant and chemosensitive cell variants, but did not alter cellular sensitivity to TN F-a. However, we determined that the sphingolipid ceramide, a natural inhibitor of PKC and Pl3K, was able to induce cell death equally in both cells variants, suggesting that it is a tool to overcome chemoresistance in these cells. Cell death occurred through activation of the mitochondrial pathway of apoptosis. Treatment with ceramide resulted in a decreased the phosphorylation of Akt, but did not alter the phosphorylation of PKC. Last, the efficacy of ceramide to induce apoptosis was increased using novel ceramide analogs.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2003
- Accession Number
- ADA424813
Entities
People
- Amanda P. Parker
- Barbara Beckman
Organizations
- Tulane University of Louisiana