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    Understanding the metabolic basis of drug resistance: therapeutic induction of the Warburg effect kills cancer cells.

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    Authors
    Martinez-Outschoorn, U E
    Lin, Z
    Ko, Y H
    Goldberg, A F
    Flomenberg, N
    Wang, C
    Pavlides, S
    Pestell, R G
    Howell, Anthony
    Sotgia, F
    Lisanti, M P
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    Affiliation
    The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center; Thomas Jefferson University, Philadelphia, PA, USA.
    Issue Date
    2011-08-01
    
    Metadata
    Show full item record
    Abstract
    Previously, we identified a form of epithelial-stromal metabolic coupling, in which cancer cells induce aerobic glycolysis in adjacent stromal fibroblasts, via oxidative stress, driving autophagy and mitophagy. In turn, these cancer-associated fibroblasts provide recycled nutrients to epithelial cancer cells, "fueling" oxidative mitochondrial metabolism and anabolic growth. An additional consequence is that these glycolytic fibroblasts protect cancer cells against apoptosis, by providing a steady nutrient stream of to mitochondria in cancer cells. Here, we investigated whether these interactions might be the basis of tamoxifen-resistance in ER(+) breast cancer cells. We show that MCF7 cells alone are Tamoxifen-sensitive, but become resistant when co-cultured with hTERT-immortalized human fibroblasts. Next, we searched for a drug combination (Tamoxifen + Dasatinib) that could over-come fibroblast-induced Tamoxifen-resistance. Importantly, we show that this drug combination acutely induces the Warburg effect (aerobic glycolysis) in MCF7 cancer cells, abruptly cutting off their ability to use their fuel supply, effectively killing these cancer cells. Thus, we believe that the Warburg effect in tumor cells is not the "root cause" of cancer, but rather it may provide the necessary clues to preventing chemo-resistance in cancer cells. Finally, we observed that this drug combination (Tamoxifen + Dasatinib) also had a generalized anti-oxidant effect, on both co-cultured fibroblasts and cancer cells alike, potentially reducing tumor-stroma co-evolution. Our results are consistent with the idea that chemo-resistance may be both a metabolic and stromal phenomenon that can be overcome by targeting mitochondrial function in epithelial cancer cells. Thus, simultaneously targeting both (1) the tumor stroma and (2) the epithelial cancer cells, with combination therapies, may be the most successful approach to anti-cancer therapy. This general strategy of combination therapy for overcoming drug resistance could be applicable to many different types of cancer.
    Citation
    Understanding the metabolic basis of drug resistance: therapeutic induction of the Warburg effect kills cancer cells. 2011, 10 (15):2521-8 Cell Cycle
    Journal
    Cell Cycle
    URI
    http://hdl.handle.net/10541/230918
    DOI
    10.4161/cc.10.15.16584
    PubMed ID
    21768775
    Type
    Article
    Language
    en
    ISSN
    1551-4005
    ae974a485f413a2113503eed53cd6c53
    10.4161/cc.10.15.16584
    Scopus Count
    Collections
    All Christie Publications
    Medical Oncology

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