1. Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model.
- Author
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Waugh Kinkade, Carolyn, Castillo-Martin, Mireia, Puzio-Kuter, Anna, Jun Yan, Foster, Thomas H., Hui Gao, Yvonne Sun, Xuesong Ouyang, Gerald, William L., Cordon-Cardo, Carlos, Abate-Shen, Cory, Kinkade, Carolyn Waugh, Yan, Jun, Gao, Hui, Sun, Yvonne, and Ouyang, Xuesong
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UROLOGY , *PROSTATE cancer , *GENITOURINARY diseases , *LABORATORY rats , *CANCER cells , *CELL lines , *CELL culture - Abstract
The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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