The Significance of PKGIB in cGMP Induced Death of Breast Cancer Cells

Abstract

The cGMP signaling pathway has been shown to be effective in the induction of breast cancer cell death. The mechanism through which cGMP causes cell death remains unknown. However, activation of cGMP-dependent protein kinase (PKG) is thought to play an important role. The following experiments will study the importance of PKG for the anticancer activity of cGMP signaling in breast cancer cells. PKGI-specific siRNA will be used to knockdown the expression of the protein. We have confirmed that three days of treatment with siRNA in MDA-MB-231 breast cancer cells causes a significant decrease in the amount of PKGIβ, the most highly expressed form of this protein in these cells, as determined by a Western blot. Cells expressing PKGIβ and with knockdown of PKGIβ will be treated with sulindac sulfide, MY5445, and NOR- 3, compounds known to activate cGMP signaling in breast cancer cells. We will then measure the effects of knockdown on sensitivity of the cells to the anticancer activity of cGMP signaling activation. These studies will determine if PKG is necessary for mediating the death of breast cancer cells in response to cGMP signaling. Understanding how the cGMP/PKG signaling pathway results in breast cancer cell death could play a pivotal role in future drug discovery efforts by identifying novel drug targets.