Deficiency of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis
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Deficiency of malate-aspartate shuttle component SLC25A12 induces pulmonary metastasis H. Furkan Alkan1,2, Paul W. Vesely3,4, Hubert Hackl5, Johannes Foßelteder6, Daniel R. Schmidt2,7,8, Matthew G. Vander Heiden2,4,8, Martin Pichler6,9, Gerald Hoefler3,10 and Juliane G. Bogner-Strauss1,10*
Abstract Background: Aspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo. However, the impact of intracellular aspartate levels on metastasis has not been studied. We previously described that loss-of-aspartate glutamate carrier 1 (SLC25A12 or AGC1), an important component of the malate-aspartate shuttle, impairs cytosolic aspartate levels, NAD+/NADH ratio, mitochondrial respiration, and tumor growth. Here, we report the impact of AGC1-knockdown on metastasis. Results: Low AGC1 expression correlates with worse patient prognosis in many cancers. AGC1-knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells. Conclusion: This study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. In addition, it also argues that commonly known metastasis indicators, including EMT genes, cell migration, or colony formation, do not always reflect metastatic capacity in vivo. Keywords: Malate-Aspartate Shuttle, AGC1, Aralar, SLC25A12, Metastasis, Aspartate
Introduction Tumor metastasis is correlated with poor prognosis. Surgical removal of the metastatic tumors from one or more organs is challenging, and drug-resistance, induced by the new tissue environment, may occur in metastatic tumors [1]. To form metastasis, cancer cells follow a cascade of events including invading the surrounding tissue, detaching from the primary tumor, surviving in the circulation, and colonizing a distant organ [2, 3]. In addition to the bioenergetics and biosynthetic demands of cell proliferation, * Correspondence: [email protected] 1 Institute of Biochemistry, Graz University of Technology, Humboldtstrasse 46/III, 8010 Graz, Austria 10 BioTechMed-Graz, Graz, Austria Full list of author information is available at the end of the article
metastatic cells also need to adapt their metabolism to succeed in the different steps of this cascade of events [1]. Although a definitive metabolic pattern that distinguishes metastatic from non-metastatic tumors has not yet been identified, there is evidence that certain metabolic pathways could be more important for metastasis formation [2]. For instance, antioxidants such as N-acetylcysteine (NAC) increase melanoma metastasis in mice [3, 4], suggesting that suppressing oxidative stress is one requirement of distant metastasis. Consistently, inhibition of the folate pathway using methotrexate or knockdown of either ALDH1L2 (aldehyde dehydrogenase 1 family member L
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