| 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. |
| Keywords: |
signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; human tissue; protein expression; cancer growth; drug efficacy; drug potentiation; monotherapy; nonhuman; antineoplastic agents; drug targeting; cell proliferation; mouse; animals; mice; animal tissue; enzyme inhibition; models, biological; map kinase signaling system; protein kinases; embryo; protein targeting; animal experiment; animal model; bim protein; combination chemotherapy; cancer cell culture; dose-response relationship, drug; experimental mouse; prostate cancer; prostatic neoplasms; cancer inhibition; genetic engineering; enzyme inhibitors; microarray analysis; mammalian target of rapamycin; rat; carcinogenicity; proto-oncogene proteins c-akt; mitogen activated protein kinase 1; extracellular signal-regulated map kinases; upregulation; cancer tissue; disease models, animal; rapamycin; hormones; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; experimental model
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