Abstract
Human 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) is the gene identified from adipose tissue in 2007. We found AGPAT9 expression was significantly higher in poorly invasive MCF7 human breast cancer cells than the highly invasive MDA-MB-231 cells. AGPAT9 significantly inhibited the proliferation of breast cancer cells in vitro and in vivo. Live-cell imaging and transwell assays showed that AGPAT9 could significantly inhibit the migration and invasive capacities of breast cancer cells. The inhibitory effect of AGPAT9 on metastasis was also observed in vivo in lung metastasis model. AGPAT9 inhibited breast cancer cell proliferation, migration and invasion through, at least in part, suppressing the V-ATPase activity. In addition, increased AGPAT9 expression in MCF-7/ADR cells could increase the chemosensitivity to doxorubicin (Dox). Our findings suggest that increasing AGPAT9 expression may be a new approach that can be used for breast cancer treatment.
Highlights
Breast cancer is the most frequent malignancy in women and the second-leading cause of cancer-related deaths [1]
We found acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) expression was significantly higher in poorly invasive MCF7 human breast cancer cells than the highly invasive MDA-MB-231 cells
We found that AGPAT9 expression was markedly different between MCF7 and MDA-MB-231
Summary
Breast cancer is the most frequent malignancy in women and the second-leading cause of cancer-related deaths [1]. The vacuolar-H+-ATPase (V-ATPase) is an important pH regulatory complex in tumor cells and positively correlated to cancer invasion and metastasis, it is required to mediate signaling pathways, such as the Wnt/β-catenin pathway [2, 3]. The low pH of tumor extracellular microenvironment may induce the increased activation of degradative enzymes, such as matrix metalloproteinases (MMPs). Low extracellular pH may promote the degradation and remolding of extracellular matrix (ECM) through proteolytic enzyme activation, contributing to cancer invasion and metastasis [4, 5]. V-ATPases are overexpressed in many types of metastatic cancers and positively correlated to their invasion and metastasis [5]. The abundance of V-ATPase on the plasma membrane correlates with an invasive phenotype [6]. There is evidence that the inhibition of V-ATPase function via knockdown of ATP6V0C (ATPase, H+ transporting, lysosomal 16kDa, V0 subunit c) expression could effectively suppress cancer metastasis by the decrease of proton extrusion and the down-regulation of protease activity [9]
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