Leucine aminopeptidase 3 promotes migration and invasion of breast cancer cells through upregulation of fascin and matrix metalloproteinases‐2/9 expression

Abstract

Overexpression of leucine aminopeptidase 3 (LAP3) is involved in proliferation, migration, and invasion of several tumor cells and plays a crucial role in tumor metastasis. However, the related mechanism remains unknown. In this study, we used MDA-MB-231 and MCF7 breast cancer cell lines to explore the role of LAP3 in the regulation of cancer cell migration and invasion by employing the natural LAP3 inhibitor bestatin and a lentivirus vector that overexpresses or knocks down LAP3. Bestatin inhibited tumor cell migration and invasion in a dose-dependent manner. Western blot assay showed that bestatin and knockdown of LAP3 upregulated phosphorylation of Hsp27 and downregulated expression of fascin. Phosphorylation of Akt and expression of matrix metalloproteinase-2/9 can also be downregulated. LAP3 overexpression showed the opposite results. Immunohistochemistry analysis was conducted to detect expression levels of LAP3 in breast cancer tissues. High LAP3 expression was correlated with the grade of malignancy. Findings of this study uncovered the molecular mechanism of LAP3 on breast cancer metastasis and indicated that LAP3 may act as a potential antimetastasis therapeutic target.fascin, leucine aminopeptidase 3 (LAP3), matrix metalloproteinases-2/9 (MMP-2/9), metastasis, signaling transduction J Cell Biochem. 2019;120:3611-3620.wileyonlinelibrary.com/journal/jcb

Melflufen, a peptide‐conjugated alkylator, is an efficient anti‐neo‐plastic drug in breast cancer cell lines

“…Fang and colleagues just recently showed that LAP3 is involved in migration and invasion of breast cancer cells. 25 Accordingly, we demonstrated that knock down of LAP3 and DPP7 in D492HER2 cells reduced the positive activity of melflufen indicating that other aminopeptidases could play a role in breast cancer treatment, an important finding which needs further evaluation.When compared to the commonly used breast cancer drug doxorubicin we were able to show that melflufen is more potent both in vitro and in vivo. D492, D492HER2, and MDA-MB231 cell lines were more sensitive to melflufen than doxorubicin, both in monolayer and in 3D culture.…”

Aminopeptidase Expression in Multiple Myeloma Associates with Disease Progression and Sensitivity to Melflufen

“…LAP3 is also implicated in antigen and major histocompatibility complex class I peptide processing, and is associated with the proinflammatory effects of IFN-γ [32]. In cancer, LAP3 has also been linked to tumor cell proliferation, migration, and invasion [33,34]. Altered LAP3 expression has also been observed in esophageal squamous cell and hepatocellular carcinoma [35,36].…”

RUNX3 Inhibits the Invasion and Metastasis of Human Colon Cancer HT‐29 Cells by Upregulating MMP‐2/9

“…In addition, RUNX3 is involved in the regulation of epithelial-mesenchymal transition (EMT) by Evidence-Based Complementary and Alternative Medicine directly regulating the transcription of blocking protein-1, thus inhibiting tumor invasion and metastasis by protecting nesting apoptosis [22]. MMP-2 can break the degradation balance of matrix, induce cancer cells to penetrate the barrier formed by extracellular matrix and basement membrane, and reduce the adhesion between cells, so that cancer cells can infiltrate, invade, and metastasize to distant organs in surrounding tissues [23,24]. In the process of degradation, large amounts of vascular endothelial growth factors stored in the extracellular matrix can be released to induce tumor angiogenesis and provide the necessary nutritional basis and pathway for tumor cell invasion [25].…”