Abstract
BackgroundAspartate 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.ResultsLow 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.ConclusionThis 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.
Highlights
Tumor metastasis is correlated with poor prognosis
Our previous findings suggest that having the adequate conditions and the substrate available for aspartate synthesis and the ability of the mitochondria to export its aspartate to the cytosol can be a limitation for cell proliferation [16]. In this follow-up study, we report that aspartate-glutamate carrier 1 (AGC1) knockdown (KD) in mouse Lewis lung carcinoma (LLC1) cells leads to increased lung metastasis and poor overall survival of syngeneic mice, despite impaired subcutaneous tumor growth
Low AGC1 expression correlates with worse prognosis in some cancers We previously generated shRNA-mediated knockdowns (KD) of mitochondrial aspartate-glutamate carrier 1 (AGC1) and observed that AGC1-KD inhibited Lewis Lung Carcinoma (LLC1) tumor growth [15]
Summary
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]. 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 [6]. 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 [7]. 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. We report the impact of AGC1-knockdown on metastasis
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