Tubulin polymerizing agents (TPA) taxotere and Epothilone B (EpoB) are highly active drugs against human breast cancer. Intracellularly, these agents bind to beta tubulin, promote microtubule bundling and induce mitotic arrest, which triggers the intrinsic (mitochondrial) pathway of apoptosis. However, the molecular mechanisms that link TPA-induced microtubular damage and mitotic arrest to the mitochondrial release of the death promoters, e.g., cytochrome c (cyt c), Smac and Omi/HtrA2, which promote the activation of effector caspases involved in apoptosis, remain to be elucidated. Survivin is a member of the antiapoptotic IAP family, and Bim is a BH3-only pro-apoptotic member of the Bcl-2 family of proteins; both are associated with the microtubules of the mitotic spindle. While downregulation of survivin levels induces apoptosis and sensitizes cancer cells to TPA, microtubule damage induces Bim to translocate to the mitochondria and neutralize the anti-apoptotic activity of Bcl-2/Bcl-XL. Recently, exposure to flavopiridol (FP), which depletes the levels of IAP and some Bcl-2 family members, following treatment with TPA has been shown to enhance TPA induced apoptosis. The working hypothesis of this project is that the strategies that downregulate survivin levels and/or function, or reduce the level and/or function of the antiapoptotic Bcl-2 and IAP proteins, would potentiate TPA-induced apoptosis as well as improve the clinical response of TPA + FP-based therapy of breast cancer.
The specific aims of the project are: 1) To determine the role of survivin and Aurora 2 kinase during TPA-induced in vitro mitotic arrest and apoptosis of human breast cancer cells. 2) To determine the role of Bim and Bcl-2 family of proteins as therapeutic targets in potentiating TPA-induced in vitro mitochondrial signaling for apoptosis in breast cancer cells. 3) To determine the effects of in vitro modulation of the levels and activity of the IAP family of proteins on TPA-induced apoptosis in human breast cancer cells. 4) To determine the predictive value of the expression of survivin, Bim, Aurora 2 kinase, Bcl-2 and IAP family of proteins for the clinical response to treatment with the sequential combination of taxotere and flavopiridol in patients with stage IV breast cancers. These translational studies would elucidate the molecular determinants that are not only predictors of response to TPA + FP but may also be promising therapeutic targets in novel treatments of human breast cancer.
| Yang, Yonghua; Rao, Rehka; Shen, Jie et al. (2008) Role of acetylation and extracellular location of heat shock protein 90alpha in tumor cell invasion. Cancer Res 68:4833-42 |
