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    Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells: Implications for preventing chemotherapy resistance.

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    Authors
    Ko, Y
    Lin, Z
    Flomenberg, N
    Pestell, R
    Howell, Anthony
    Sotgia, F
    Lisanti, M
    Martinez-Outschoorn, U
    Affiliation
    Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.
    Issue Date
    2011-12-15
    
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    Abstract
    Glutamine metabolism is crucial for cancer cell growth via the generation of intermediate molecules in the tricarboxylic acid (TCA) cycle, antioxidants and ammonia. The goal of the current study was to evaluate the effects of glutamine on metabolism in the breast cancer tumor microenvironment, with a focus on autophagy and cell death in both epithelial and stromal compartments. For this purpose, MCF7 breast cancer cells were cultured alone or co-cultured with non-transformed fibroblasts in media containing high glutamine and low glucose (glutamine +) or under control conditions, with no glutamine and high glucose (glutamine --). Here, we show that MCF7 cells maintained in co-culture with glutamine display increased mitochondrial mass, as compared to control conditions. Importantly, treatment with the autophagy inhibitor chloroquine abolishes the glutamine-induced augmentation of mitochondrial mass. It is known that loss of caveolin-1 (Cav-1) expression in fibroblasts is associated with increased autophagy and an aggressive tumor microenvironment. Here, we show that that Cav-1 down-regulation which occurs in fibroblasts maintained in co-culture specifically requires glutamine. Interestingly, glutamine increases the expression of autophagy markers in fibroblasts, but decreases expression of autophagy markers in MCF7 cells, indicating that the glutamine regulates the autophagy program in a compartment-specific manner. Functionally, glutamine protects MCF7 cells against apoptosis, via the up-regulation of the anti-apoptotic and anti-autophagic protein TIGAR. Also, we show that glutamine cooperates with stromal fibroblasts to confer tamoxifen-resistance in MCF7 cancer cells. Finally, we provide evidence that co-culture with fibroblasts i) promotes glutamine catabolism and ii) decreases glutamine synthesis, in MCF7 cancer cells. Taken together, our findings suggest that autophagic fibroblasts may serve as a key source of energy-rich glutamine to fuel cancer cell mitochondrial activity, driving a vicious cycle of catabolism in the tumor stroma and anabolic tumor cell expansion.
    Citation
    Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells: Implications for preventing chemotherapy resistance. 2011, 12 (12):1085-1097 Cancer Biol Ther
    Journal
    Cancer Biology & Therapy
    URI
    http://hdl.handle.net/10541/230783
    DOI
    10.4161/cbt.12.12.18671
    PubMed ID
    22236876
    Type
    Article
    Language
    en
    ISSN
    1555-8576
    ae974a485f413a2113503eed53cd6c53
    10.4161/cbt.12.12.18671
    Scopus Count
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