Rapamycin and its analogs, all of which inhibit the mammalian target of rapamycin (mTOR) protein, are demonstrating exciting results in anticancer chemotherapy clinical trials, especially against solid tumors such as kidney and lung cancer. Combination therapy is often the protocol of choice for chemotherapy treatment, both to circumvent resistance mechanisms and to enhance cell death produced by a single drug alone. This proposal aims to evaluate inhibition of 14-3-3 as a novel way to enhance rapamycin-induced cell death. 14-3-3 is a critical cell survival protein, shown to be upregulated in many cancers. The mechanism by which cell death is increased in the presence of both mTOR and 14-3-3 inhibitors will be examined, mainly by determining the extent by which 14-3-3 may regulate the mTOR signaling pathway. Several lung cancer cell lines will be utilized to dissect these interactions both in vivo and in vitro. By establishing the importance of 14-3-3 on mTOR signaling, this work will serve to validate 14-3-3 as an important target for anticancer chemotherapeutics.
| Cockrell, L M; Puckett, M C; Goldman, E H et al. (2010) Dual engagement of 14-3-3 proteins controls signal relay from ASK2 to the ASK1 signalosome. Oncogene 29:822-30 |
