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

Department of Urology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 10/2008; 118(9):3051-64. DOI: 10.1172/JCI34764
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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.

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Available from: Mireia Castillo-Martin, Aug 27, 2015
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    • "In preclinical breast and prostate cancer murine models, inhibition of mTORC1, which is composed of regulatoryassociated protein of mTOR (RAPTOR), mLST8 (also known as GbL), and AKT substrate of 40 kDa (PRAS40), with the mTORi rapamycin, led to MAPK pathway activation through a PI3K- dependent feedback loop. However, when rapamycin was combined with the MEK1/2 inhibitor, PD0325901, MAPK feedback activation was abrogated and resulted in an enhanced antitumoral effect (Carracedo et al, 2008; Kinkade et al, 2008). "
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    • "Consistent with our conclusion that ERK1/2 inhibition by lovastatin is at least partly responsible for apoptosis induction in PCC cells, Zitzmann et al. (2010) also showed a significant decrease in cell viability, inhibition of cell proliferation and induction of apoptosis in human midgut (GOT), pancreatic (BON) and broncho-pulmonary (H727) NET cell lines through RAF/MEK/ERK1/2 pathway inhibition with the RAF1 inhibitor RAF265: interestingly, there was no correlation between measured basal ERK activity and sensitivity to RAF265. In several other solid tumours such as breast and prostate cancer (Carracedo et al. 2008, Kinkade et al. 2008) and in leukaemia (Steelman et al. 2008), RAF/MEK/ERK pathway inhibition, especially in combination with mTOR inhibition, has also been found to have crucial antitumour potential (Grant 2008, Ricciardi et al. 2012). Moreover, it has recently been reported that generation of reactive oxygen species and downstream activation of RAS/RAF/ERK and RAS/PI3K pathways by silibinin could prevent apoptosis in PCC (PC12) cells (Liu et al. 2011). "
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    ABSTRACT: Currently, there is no completely effective therapy available for metastatic phaeochromocytomas (PCCs) and paragangliomas. In this study, we explore new molecular targeted therapies for these tumours, using one more benign (mouse phaeochromocytoma cell (MPC)) and one more malignant (mouse tumour tissue (MTT)) mouse PCC cell line - both generated from heterozygous neurofibromin 1 knockout mice. Several PCC-promoting gene mutations have been associated with aberrant activation of PI3K/AKT, mTORC1 and RAS/RAF/ERK signalling. We therefore investigated different agents that interfere specifically with these pathways, including antagonism of the IGF1 receptor by NVP-AEW541. We found that NVP-AEW541 significantly reduced MPC and MTT cell viability at relatively high doses but led to a compensatory up-regulation of ERK and mTORC1 signalling at suboptimal doses while PI3K/AKT inhibition remained stable. We subsequently investigated the effect of the dual PI3K/mTORC1/2 inhibitor NVP-BEZ235, which led to a significant decrease of MPC and MTT cell viability at doses below 50 nM but again increased ERK signalling. Accordingly, we next examined the combination of NVP-BEZ235 with the established agent lovastatin, as this has been described to inhibit ERK signalling. Lovastatin alone significantly reduced MPC and MTT cell viability at therapeutically relevant doses and inhibited both ERK and AKT signalling, but increased mTORC1/p70S6K signalling. Combination treatment with NVP-BEZ235 and lovastatin showed a significant additive effect in MPC and MTT cells and resulted in inhibition of both AKT and mTORC1/p70S6K signalling without ERK up-regulation. Simultaneous inhibition of PI3K/AKT, mTORC1/2 and ERK signalling suggests a novel therapeutic approach for malignant PCCs.
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    • "However, piceatannol inhibited p-S6 (Ser235/236) expression in LNCaP and PC- 3 cells (Figure 3(c)). Since AKT is an upstream modulator and activator of mTOR [41] [42], we analyzed changes in AKT expression. A dose-dependent suppression of total and Thr308-phosphorylated AKT was found in all three CaP cells treated by piceatannol (Figure 3(d)). "
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