Inhibition of PKR Activity is Required for Survival of Breast Cancer
Final rept. 1 Jul 2001-31 Dec 2002
NORTHWESTERN UNIV EVANSTON IL
Pagination or Media Count:
PKR is an interferon-inducible protein kinase, which has recently been discovered to have pleiotropic effects on the growth and differentiation of normal and neoplastic cells. We reported a direct correlation between PKR expression and differentiation in a variety of human tumors and in normal squamous epithelial, and an inverse association betweenPKR expression and proliferation in head and neck cancer. The mechanisms by which PKR produced such effects are being intensively studied. Phosphorylation of its major substrate, eIF-2alpha, leads to a selective inhibition of protein synthesis. PKR also phosphorylates IkB, freeing NFkB to tranlocate to the nucleus and induce transcription of a number of gene products. PKR-induced apoptosis has recently been reported to be co-dependent on both the eIF2alpha and NFKB pathways in HeLa cells. Breast cancer was utilized as a model system to determine the role of PKR in loss of hormone and growth factor dependence in human cancers, as it appears inactive or hypoactive, as determined by eIF-2alpha phosphyorylation in this system. We hypothesized that hormone deprivation induces apoptosis in dependent cell lines through a PKR NFKB mediated process, but this pathway is abrogated in hormone-independent cell lines.
- Medicine and Medical Research