Date of Graduation
Davis College of Agriculture, Natural Resources and Design
Protein kinase C (PKC) is a family of serine/threonine kinases composed of 12 unique isoforms that function in a variety of cellular processes including proliferation, apoptosis, differentiation and carcinogenesis. The contribution of individual PKC isoforms to these processes is largely unexplored. The purpose of this study is to identify specific PKC isoforms that promote breast tumor cell survival following radiation treatment. This work demonstrated that depletion of PKC delta and PKC zeta isoforms from MCF-7 and MDA-MB-231 human breast tumor cells by antisense oligonucleotides significantly impaired survival following radiation insult. Antisense oligonucleotides were shown to be effective and selective inhibitors of specific PKC isoforms. The PKC delta inhibitor, rottlerin reduced cell survival and confirmed that PKC delta inhibition attenuates breast tumor cell survival, both in the presence and absence of radiation insult. Inhibition of PKC zeta significantly reduced the survival of radiation treated breast tumor cells. DNA damage, assessed using the comet assay provided evidence that depletion of PKC delta from MDA-MB-231 cells results in loss of DNA integrity. In contrast, PKC zeta antisense oligonucleotide treatment did not result in DNA damage. Consistent with participation in cell survival, PKC delta protein levels were elevated in response to radiation treatment. These studies have identified two PKC isoforms that function in breast tumor cell survival and support the application of isoform specific PKC inhibitors to the treatment of human breast tumors.
McCracken, Meredith Ann, "Role of protein kinase C isoforms in human breast tumor cell survival" (2002). Graduate Theses, Dissertations, and Problem Reports. 1609.