Silence of α1-Antitrypsin Inhibits Migration and Proliferation of Triple Negative Breast Cancer Cells

Abstract

Backgroundα1-antitrypsin (α1-AT) is highly expressed in many tumors. However, to the best of our knowledge, its relationship to triple negative breast cancer (TNBC) has not yet been studied. Thus, in this research we first explored the influence of α1-AT silencing on the abilities of migration and invasion, and then further study its molecular mechanism in TNBC cells.Material/MethodsThe viability of MDA-MB-231 cells were detected using cell counting kit-8 (CCK-8). The abilities of migration and invasion were examined by Transwell assay. The metastasis-related factors were tested respectively by quantitative real-time PCR (qRT-PCR) and western blot assays.ResultsOur study results showed that α1-AT level in TNBC tissues was higher than non-triple negative breast cancer (n-TNBC) and adjacent normal breast tissues. The high expression of α1-AT was linked to type of cancer, tumor size, TNM stage and metastasis, but was not correlated with α1-AT expression and age. si-α1-AT suppressed the viability, migration, and invasion of cells. While si-α1-AT upregulated E-cadherin and the tissue inhibitor of metalloproteinases-2 (TIMP-2) levels, it downregulated metastasis associated 1 (MTA1), matrix metallopeptidase 2 (MMP2), phosphorylated-mammalian target of rapamycin (p-mTOR), phosphorylated-protein kinase B (p-Akt), and phosphorylated-phosphatidylinositol 3 kinase (p-PI3K) levels. We also found that the PI3K/Akt/mTOR pathway activator reversed the role of si-α1-AT in metastasis-related factors.Conclusionsα1-AT was highly expressed in TNBC tissues, and its silencing suppressed the abilities of migration and invasion in TNBC cells and downregulated the PI3K/Akt/mTOR pathway. Thus, α1-AT may have a potential therapeutic effect on TNBC.

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process

“…The fact that they reduce the expression of MMPs while increasing that of TIMPs makes HIV-protease inhibitors similar to natural compounds that perform these actions thanks to the same ability to hamper the AKT and MAPK signaling pathways [ 202 , 203 ]. Also, synthetic antagonists of α1-antitrypsin, an endogenous protease inhibitor which is overexpressed in tumor tissues, downregulate MMPs and, at the same time, upregulate TIMPs via PI3K/AKT inhibition [ 204 ]. It is worthy of note that the HIV-protease inhibitor ritonavir reduces α1-antitrypsin protein levels in treated patients [ 205 ].…”

Mechanisms behind Retinal Ganglion Cell Loss in Diabetes and Therapeutic Approach

“…In diabetic retinopathy there is a downregulation of Akt activity affecting a large number of pathways related to diverse cellular processes; ultimately, the resulting imbalance promotes RGC apoptosis. In the literature there are reports stating that A1AT can downregulate the PI3K/Akt/mTOR pathway in breast cancer cells, where this pathway is increased [163,164]. However, there are other reports remarking the role of A1AT as an up-regulator of the PI3K/Akt pathway, reducing neutrophil elastase-induced migration of lung cancer cells, tumor tissue proliferation and inflammatory microenvironment [161,162].…”

Association between α1‑antitrypsin and acute coronary syndrome

“…An increase in AAT expression may also contribute to activation of signaling events that initiate the production and release of pro-inflammatory cytokines and adhesion molecules, such as lipopolysaccharides, TNF-α, IL-1 and IL-6, which are released by neutrophils, monocytes, macrophages and alveolar macrophages that may in turn activate innate immunity and inflammatory responses ( 13-15 ). A number of studies have suggested that AAT is associated with the development of chronic hepatitis, liver cirrhosis ( 16 ), chronic obstructive pulmonary disease ( 17 ), atherosclerotic diseases ( 18 ), tumors ( 19 ) and autoimmune diseases ( 20 ).…”