Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
Carolyn Waugh Kinkade, Mireia Castillo-Martin, Anna Puzio-Kuter, Jun Yan, Thomas H. Foster, Hui Gao, Yvonne Sun, Xuesong Ouyang, William L. Gerald, Carlos Cordon-Cardo, Cory Abate-Shen
Carolyn Waugh Kinkade, Mireia Castillo-Martin, Anna Puzio-Kuter, Jun Yan, Thomas H. Foster, Hui Gao, Yvonne Sun, Xuesong Ouyang, William L. Gerald, Carlos Cordon-Cardo, Cory Abate-Shen
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Research Article

Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model

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.

Authors

Carolyn Waugh Kinkade, Mireia Castillo-Martin, Anna Puzio-Kuter, Jun Yan, Thomas H. Foster, Hui Gao, Yvonne Sun, Xuesong Ouyang, William L. Gerald, Carlos Cordon-Cardo, Cory Abate-Shen

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Figure 8

AKT/mTOR pathway activation is associated with human prostate cancer progression and correlated with activation of ERK MAPK.

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AKT/mTOR pathway activation is associated with human prostate cancer pro...
(A–L) Expression of PTEN and components on the AKT/mTOR signaling pathway in human normal and primary prostate cancer samples. Representative adjacent sections from the specimens used for the TMAs show staining for the indicated proteins. Shown are examples of benign prostatic tissue (Normal), a tumor without activation of the PTEN/AKT/mTOR pathway (Tumor 1), and a tumor with activation of this pathway (Tumor 2). Note that the expression of PTEN is inversely correlated with expression of p-AKT, p-mTOR, and p-S6. (M–O) Expression of p-ERK activation on semiadjacent sections of the same specimens. Note that, in these samples, p-ERK activation is well correlated with activation of components of the AKT/mTOR signaling pathway. Scale bar: 100 μm.