In our previous study, we determined that blocking glutamine metabolism and/or inhibiting cytosolic aspartate delivery via knockdown of mitochondrial aspartate-glutamate carrier 1 (AGC1) impairs cell proliferation and tumor growth. In addition, glutamine is an important substrate for mitochondrial aspartate synthesis. Cells lacking mitochondrial respiration have low aspartate levels and slow proliferation. For example, one requirement for aspartate production is a suitable NAD +/NADH ratio. Therefore, endogenous aspartate synthesis can limit the growth of some tumors. Although aspartate is available in circulation, these levels are insufficient to trigger its uptake in most cells that lack the plasma membrane aspartate transporter SLC1A3. Intracellular aspartate levels correlate with the proliferation rate in cancer cells and are limiting for the growth of some tumors in vivo. Aspartate is also involved in several intracellular processes including, but not limited to, redox homeostasis and the urea cycle. Īspartate is a proteinogenic non-essential amino acid that is used for de novo synthesis of nucleotides and certain non-essential amino acids. Furthermore, asparagine levels or ASNS (asparagine synthetase) activity could also determine the metastatic capacity of breast cancers both in vivo and in vitro. Pyruvate was also shown to be an important mediator of metastatic niche formation through hydroxylation of collagen. In addition, proline catabolism is selectively important for the proliferation and colony formation of metastatic cells, and reduced Prodh (proline dehydrogenase) activity leads to impaired in vivo lung metastasis in mouse breast cancer tumors. Similarly, lactate uptake through MCT1 (monocarboxylate transporter 1) expression has no effect on primary tumor growth but improves the number of circulating tumor cells and promotes distant melanoma metastasis. Consistently, inhibition of the folate pathway using methotrexate or knockdown of either ALDH1L2 (aldehyde dehydrogenase 1 family member L2) or MTHFD1 (methylenetetrahydrofolate dehydrogenase) blocks melanoma metastasis in vivo via hindering the survival of circulating melanoma tumors while having no impact on subcutaneous tumor growth. For instance, antioxidants such as N-acetylcysteine (NAC) increase melanoma metastasis in mice, suggesting that suppressing oxidative stress is one requirement of distant metastasis. 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. In addition to the bioenergetics and biosynthetic demands of cell proliferation, metastatic cells also need to adapt their metabolism to succeed in the different steps of this cascade of events. 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. 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. Tumor metastasis is correlated with poor prognosis. 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. This study highlights that certain branches of metabolism impact tumor growth and tumor metastasis differently. On the other hand, conventional in vitro metastasis assays show no indication of increased metastasis capacity of AGC1-knockdown cells. AGC1-knockdown in mouse lung carcinoma and melanoma cell lines leads to increased pulmonary metastasis following subcutaneous or intravenous injections, respectively. Low AGC1 expression correlates with worse patient prognosis in many cancers. Here, we report the impact of AGC1-knockdown on metastasis. 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. However, the impact of intracellular aspartate levels on metastasis has not been studied. Aspartate biosynthesis and its delivery to the cytosol can be crucial for tumor growth in vivo.
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