mTOR Complex 2 Is Required for the Development of Prostate Cancer Induced by Pten Loss in Mice

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Cancer cell (Impact Factor: 23.52). 03/2009; 15(2):148-59. DOI: 10.1016/j.ccr.2008.12.017
Source: PubMed


mTOR complex 2 (mTORC2) contains the mammalian target of rapamycin (mTOR) kinase and the Rictor regulatory protein and phosphorylates Akt. Whether this function of mTORC2 is critical for cancer progression is unknown. Here, we show that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice. Furthermore, we find that Rictor is a haploinsufficient gene and that deleting one copy protects Pten heterozygous mice from prostate cancer. Finally, we show that the development of prostate cancer caused by Pten deletion specifically in prostate epithelium requires mTORC2, but that for normal prostate epithelial cells, mTORC2 activity is nonessential. The selective requirement for mTORC2 in tumor development suggests that mTORC2 inhibitors may be of substantial clinical utility.

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Available from: Mark A Magnuson, Feb 11, 2014
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    • "Conditional knockout of mTOR in a mouse model of PCa caused by deletion of PTEN inhibits prostate tumorigenesis, demonstrating the requirement for an intact signaling axis to drive cellular transformation in prostate epithelial cells.72 Interestingly, others have demonstrated that concurrent loss of PTEN and RICTOR, a defining component of the mTORC2 complex, reduces the incidence of PCa formation in mice.73 Thus, PI3K-AKT-mTOR hyperactivation is sufficient to induce PCa formation, and both mTORC1 and mTORC2 are necessary to facilitate this process in vivo. "
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    ABSTRACT: Prostate cancer (PCa) is the second most common malignancy among men in the world. Castration-resistant prostate cancer (CRPC) is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy (ADT). Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor (AR) signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.
    Asian Journal of Andrology 04/2014; 16(3). DOI:10.4103/1008-682X.122876 · 2.60 Impact Factor
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    • "There are reports that mTORC2 is required for development of certain cancers with PTEN loss [26]. C33A cells are PTEN defective, and we found that SC-66 is a potent mTORC2 inhibitor. "
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    ABSTRACT: PI3K/AKT pathway alterations are associated with incomplete response to chemoradiation in human cervical cancer. This study was performed to test for mutations in the PI3K pathway and to evaluate the effects of AKT inhibitors on glucose uptake and cell viability. Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (PIK3CAR88Q and PTENR233*) were treated with increasing concentrations of two allosteric AKT inhibitors (SC-66 and MK-2206) with or without the glucose analogue 2-deoxyglucose (2-DG). Cell viability and activation status of the AKT/mTOR pathway were determined in response to the treatment. Glucose uptake was evaluated by incubation with 18F-fluorodeoxyglucose (FDG). Cell migration was assessed by scratch assay. Activating PIK3CA (E545K, E542K) and inactivating PTEN (R233*) mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56%) and MK-2206 (30 µM-49%) treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment. The mutational spectrum of the PI3K/AKT pathway in cervical cancer is complex. AKT inhibitors effectively block mTORC1/2, decrease glucose uptake, glycolysis, and decrease cell viability in vitro. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer.
    PLoS ONE 04/2014; 9(4):e92948. DOI:10.1371/journal.pone.0092948 · 3.23 Impact Factor
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    • "While the relevance of mTORC1 to human carcinogenesis has been well-documented, whether mTORC2 is critical to human cancer development remains unknown. Recently, RICTOR, the unique structure of mTORC2, was found to be necessary to the tumor formation of PTEN-deficient prostate epithelial cells in nude mice, indicating that mTORC2 can function in synergy with PI3K to promote tumorigenesis [50]. In addition, inhibition of mTORC2 reduced proliferation and anchorage-independent growth of human cancer cells by inducing downregulation of cyclin D1 and cell cycle arrest at G1 phase [51]. "
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    ABSTRACT: As the fifth most common cancer in men and the eighth most common cancer in women, hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, with standard chemotherapy and radiation being minimally effective in prolonging survival. Virus hepatitis, particularly HBV and HCV infection is the most prominent risk factor for HCC development. Mammalian target of rapamycin (mTOR) pathway is activated in viral hepatitis and HCC. mTOR inhibitors have been tested successfully in clinical trials for their antineoplastic potency and well tolerability. Treatment with mTOR inhibitor alone or in combination with cytotoxic drugs or targeted therapy drug scan significantly reduces HCC growth and improves clinical outcome, indicating that mTOR inhibition is a promising strategy for the clinical management of HCC.
    04/2014; 2014(34):735672. DOI:10.1155/2014/735672
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