Article

Glutamine Sensitivity Analysis Identifies the xCT Antiporter as a Common Triple-Negative Breast Tumor Therapeutic Target

UCSF/Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA. Electronic address: .
Cancer cell (Impact Factor: 23.52). 10/2013; 24(4). DOI: 10.1016/j.ccr.2013.08.020
Source: PubMed

ABSTRACT

A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on one-third of triple-negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory sulfasalazine decreases tumor growth, revealing a therapeutic target in breast tumors of poorest prognosis and a lead compound for rapid, effective drug development.

Download full-text

Full-text

Available from: Anneleen Daemen
  • Source
    • "This also leads to more aerobic metabolism of tumor cells to promote their proliferation, which is opposed to Warburg's observation. Nevertheless, aerobic glycolysis seems to be common in EMT-generated cells and highly aggressive TNBCs, which are enriched for m-cars137138139140141142 . Upon EMT, carcinoma cells reprogram their metabolisms and become more dependent on glycolysis143144145. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Changes in the tumor microenvironment (TME) can trigger the activation of otherwise non-malignant cells to become highly aggressive and motile. This is evident during initial tumor growth when the poor vascularization in tumors generates hypoxic regions that trigger the latent embryonic program, epithelial-to-mesenchymal transition (EMT), in epithelial carcinoma cells (e-cars) leading to highly motile mesenchymal-like carcinoma cells (m-cars), which also acquire cancer stem cell properties. After that, specific bidirectional interactions take place between m-cars and the cellular components of TME at different stages of metastasis. These interactions include several vicious positive feedback loops in which m-cars trigger a phenotypic switch, causing normal stromal cells to become pro-tumorigenic, which then further promote the survival, motility, and proliferation of m-cars. Accordingly, there is not a single culprit accounting for metastasis. Instead both m-cars and the TME dynamically interact, evolve and promote metastasis. In this review, we discuss the current status of the known interactions between m-cars and the TME during different stages of metastasis and how these interactions promote the metastatic activity of highly malignant m-cars by promoting their invasive mesenchymal phenotype and CSC properties.
    Full-text · Article · Jan 2016 · Cancer letters
  • Source
    • "HIF induced AA transporters provide attractive, but yet unexplored, targets for the design and development of a new class of anticancer drugs. Therapies targeting these nutrient transporters are being developed that hold promise as both direct targets and factors to synergise with chemotherapy (Harris et al., 2015; Rosilio et al., 2015; Timmerman et al., 2013; Yun et al., 2014). We thus feel that this will be an important theme in future cancer discovery. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In their quest for survival and successful growth, cancer cells optimize their cellular processes to enable them to outcompete normal cells in their microenvironment. In essence cancer cells: (i) enhance uptake of nutrients/metabolites, (ii) utilise nutrients more efficiently via metabolic alterations and (iii) deal with the metabolic waste products in a way that furthers their progression whilst hampering the survival of normal tissue. Hypoxia Inducible Factors (HIFs) act as essential drivers of these adaptations via the promotion of numerous membrane proteins including glucose transporters (GLUTs), monocarboxylate transporters (MCTs), amino-acid transporters (LAT1, xCT), and acid-base regulating carbonic anhydrases (CAs). In addition to a competitive growth advantage for tumour cells, these HIF-regulated proteins are implicated in metastasis, cancer 'stemness' and the immune response. Current research indicates that combined targeting of these HIF-regulated membrane proteins in tumour cells will provide promising therapeutic strategies in the future.
    Full-text · Article · Dec 2015 · Molecular Aspects of Medicine
  • Source
    • "RPPA analysis confirmed that high expression of SLC1A5 is associated with basal-like and luminal B types of BCa, as well poorer responsiveness to therapy, whereas low SLC1A5 expression coincided with reactive, luminal type tumors. Along these lines, tumors more dependent on Gln, such as triple-negative BCa cells (Timmerman et al., 2013) and melanoma cells (Filipp et al., 2012), could benefit from therapies that target Gln-pathway components in combination with other therapies. Our data also show that RNF5-medi- ated control of Gln carrier proteins does not function in all BCa (E) MDA-MB-231 cells transfected with indicated constructs were incubated with 2.5 mg/ml BFA for 24 hr, stained with Annexin-V-EGFP and PI, and analyzed by FACS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5(hi)/SLC1A5/38A2(lo) expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Cancer cell
Show more