Matteo Morotti1, Christos E Zois2, Rokaya El-Ansari3, Madeleine L Craze3, Emad A Rakha3, Shih-Jung Fan4, Alessandro Valli2, Syed Haider2,5, Deborah C I Goberdhan4, Andrew R Green3, Adrian L Harris6. 1. Hypoxia and Angiogenesis Group, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, OX3 9DS, UK. drmorottimatteo@gmail.com. 2. Hypoxia and Angiogenesis Group, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, OX3 9DS, UK. 3. Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, NG7 2RD, UK. 4. Department of Physiology, Anatomy and Genetics, Le Gros Clark Building, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK. 5. The Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK. 6. Hypoxia and Angiogenesis Group, Weatherall Institute of Molecular Medicine, Department of Oncology, University of Oxford, Oxford, OX3 9DS, UK. aharris.lab@imm.ox.ac.uk.
Abstract
BACKGROUND: Glutamine (Gln) is an abundant nutrient used by cancer cells. Breast cancers cells and particularly triple-receptor negative breast cancer (TNBC) are reported to be dependent on Gln to produce the energy required for survival and proliferation. Despite intense research on the role of the intracellular Gln pathway, few reports have focussed on Gln transporters in breast cancer and TNBC. METHODS: The role and localisation of the Gln transporter SLC38A2/SNAT2 in response to Gln deprivation or pharmacological stresses was examined in a panel of breast cancer cell lines. Subsequently, the effect of SLC38A2 knockdown in Gln-sensitive cell lines was analysed. The prognostic value of SLC38A2 in a cohort of breast cancer was determined by immunohistochemistry. RESULTS: SLC38A2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. We confirmed an autophagic route of degradation for SLC38A2. SLC38A2 knockdown decreased Gln consumption, inhibited cell growth, induced autophagy and led to ROS production in a subgroup of Gln-sensitive cell lines. High expression of SLC38A2 protein was associated with poor breast cancer specific survival in a large cohort of patients (p = 0.004), particularly in TNBC (p = 0.02). CONCLUSIONS: These results position SLC38A2 as a selective target for inhibiting growth of Gln-dependent breast cancer cell lines.
BACKGROUND:Glutamine (Gln) is an abundant nutrient used by cancer cells. Breast cancers cells and particularly triple-receptor negative breast cancer (TNBC) are reported to be dependent on Gln to produce the energy required for survival and proliferation. Despite intense research on the role of the intracellular Gln pathway, few reports have focussed on Gln transporters in breast cancer and TNBC. METHODS: The role and localisation of the Gln transporter SLC38A2/SNAT2 in response to Gln deprivation or pharmacological stresses was examined in a panel of breast cancer cell lines. Subsequently, the effect of SLC38A2 knockdown in Gln-sensitive cell lines was analysed. The prognostic value of SLC38A2 in a cohort of breast cancer was determined by immunohistochemistry. RESULTS:SLC38A2 was identified as a strongly expressed amino acid transporter in six breast cancer cell lines. We confirmed an autophagic route of degradation for SLC38A2. SLC38A2 knockdown decreased Gln consumption, inhibited cell growth, induced autophagy and led to ROS production in a subgroup of Gln-sensitive cell lines. High expression of SLC38A2 protein was associated with poor breast cancer specific survival in a large cohort of patients (p = 0.004), particularly in TNBC (p = 0.02). CONCLUSIONS: These results position SLC38A2 as a selective target for inhibiting growth of Gln-dependent breast cancer cell lines.
Authors: Ainara Elorza; Inés Soro-Arnáiz; Florinda Meléndez-Rodríguez; Victoria Rodríguez-Vaello; Glenn Marsboom; Guillermo de Cárcer; Bárbara Acosta-Iborra; Lucas Albacete-Albacete; Angel Ordóñez; Leticia Serrano-Oviedo; Jose Miguel Giménez-Bachs; Alicia Vara-Vega; Antonio Salinas; Ricardo Sánchez-Prieto; Rafael Martín del Río; Francisco Sánchez-Madrid; Marcos Malumbres; Manuel O Landázuri; Julián Aragonés Journal: Mol Cell Date: 2012-10-25 Impact factor: 17.970
Authors: Francesca Nardi; Thorsten M Hoffmann; Clare Stretton; Emma Cwiklinski; Peter M Taylor; Harinder S Hundal Journal: J Biol Chem Date: 2015-02-04 Impact factor: 5.157
Authors: Piero Dalle Pezze; Stefanie Ruf; Annika G Sonntag; Miriam Langelaar-Makkinje; Philip Hall; Alexander M Heberle; Patricia Razquin Navas; Karen van Eunen; Regine C Tölle; Jennifer J Schwarz; Heike Wiese; Bettina Warscheid; Jana Deitersen; Björn Stork; Erik Fäßler; Sascha Schäuble; Udo Hahn; Peter Horvatovich; Daryl P Shanley; Kathrin Thedieck Journal: Nat Commun Date: 2016-11-21 Impact factor: 14.919
Authors: M van Geldermalsen; Q Wang; R Nagarajah; A D Marshall; A Thoeng; D Gao; W Ritchie; Y Feng; C G Bailey; N Deng; K Harvey; J M Beith; C I Selinger; S A O'Toole; J E J Rasko; J Holst Journal: Oncogene Date: 2015-10-12 Impact factor: 9.867