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BAD and Mcl-1 Regulation in Prostate Cancer

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BAD and Mcl-1 Regulation in Prostate Cancer
Yancey, Dana D.
Recent publications have identified the Ser112 and Ser136 residues of BAD as the convergence point for several survival signaling pathways including the PKA, EGF, and PI3K/Akt pathways in prostate cancer cells. Upon phosphorylation of these residues, BAD becomes unable to bind to and inactivate the anti-apoptotic Bcl-2 subfamily, including Bcl-2 and Bcl-xL, allowing these proteins to carry out their pro-survival function. Treatment of C42 cells with a PI3K inhibitor in the absence of survival factors results in BAD dephosphorylation within 3 hrs, however despite that fact, apoptosis becomes evident only after 12 hrs. In an attempt to decrease the amount of time it takes to induce significant apoptosis, we have found that combination treatment with both PI3K inhibitor and a protein synthesis inhibitor reduces the time of apoptosis induction to approximately 6 hrs. To elucidate the mechanism by which this interaction occurs, we examined the protein levels of the Bcl-2 family of proteins which regulates apoptosis. More specifically, we discovered that while Bcl-xL and Bcl-2 levels remain relatively stable, combination treatment causes a rapid decrease of Mcl-1 levels in androgen-independent C42 prostate cancer cells as well as other PTEN-deficient cancer cell lines. Based on this preliminary finding, we hypothesize that simultaneous BAD dephosphorylation and loss of Mcl-1 expression induce rapid apoptosis in prostate cancer cells. To support this hypothesis, we demonstrated a synergistic increase in apoptosis within a 6 hr time frame using the combination of PI3K inhibitor and protein synthesis inhibitor compared to treatment with either agent alone. Using shRNA-targeted Mcl-1 downregulation, we have been able to observe increased cell death in C42 cells with Mcl-1 loss treated with PI3K inhibitor compared to those cells that only have Mcl-1 loss or only recieved PI3K inhibition. Future studies will investigate the mechanism by which Mcl-1 levels are downregulated and will explore the role of Mcl-1 in prostate cancer. These studies will be using Mcl-1 knockout mouse model as well as prostate cancer xenografts with inducible Mcl-1-specific shRNA to extend observations made in tissue culture models to an in vivo system. It is our hope that this information could be used to develop new combinatorial anti-cancer therapeutics; while monitoring levels of Mcl-1 expression and BAD phosphorylation will permit predicting their efficacy.
Kulik, George (committee chair)
Metheny-Barlow, Linda (committee member)
Lyles, Douglas (committee member)
Pardee, Timothy (committee member)
Sui, Guangchao (committee member)
2013-01-09T09:35:13Z (accessioned)
2012 (issued)
Cancer Biology (discipline)
forever (terms)
10000-01-01 (liftdate)
http://hdl.handle.net/10339/37662 (uri)
en (iso)
Wake Forest University

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