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 7

Combination therapy is antitumorigenic in adjuvant therapy of hormone-refractory prostate cancer.

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Combination therapy is antitumorigenic in adjuvant therapy of hormone-re...
(A–I) Studies in the whole animal. (A) Diagram of the experimental strategy. Strategy is similar to that in Figure 1; however, unlike the androgen-independent treatment group, Nkx3.1+/—Pten+/— mutant mice were castrated immediately prior to receiving the rapamycin and/or PD0325901 (or vehicle) treatment. (B–G) Representative tissue sections from the Nkx3.1+/—Pten+/— mutant mice showing histological phenotype (H&E) and immunostaining for p-S6 and p-ERK, as indicated. (H) Prostate tissue weights, showing mean ± SEM, with P value indicated. (I) Percentage of proliferating cells as determined by Ki67 staining, showing mean ± SEM, with P value indicated. (J–Q) Studies done in a complementary tissue recombination model. (J) Diagram of the experimental strategy. (K–P) Representative tissue sections from the tissue recombinants made from the Nkx3.1+/—Pten+/— prostate epithelium showing histological phenotype (H&E) and immunostaining for p-S6K and p-ERK, as indicated. (Q) Weights of the tissue graphs, showing mean ± SEM, with P value indicated. Scale bars: 100 μm.