Cetyltrimethylammonium Bromide Disrupts the Mesenchymal Characteristics of HA22T/VGH CellsViaInactivation of c-Met/PI3K/Akt/mTOR Pathway

Abstract

Background/Aim: Hepatocellular carcinoma (HCC) arises from hepatocytes, and is the most frequently occurring malignancy of primary liver cancer. In this study, we investigated the anti-metastatic effects of the quaternary ammonium compound, cetyltrimethylammonium bromide (CTAB), on HA22T/VGH HCC cells. Materials and Methods: According to our preliminary data, the effect of CTAB on cell cycle distribution, migration, invasion and the associated protein levels was examined using flow cytometry, woundhealing migration, Matrigel transwell invasion assay and western blotting under sub-lethal concentrations. Results: CTAB treatment of HA22T/VGH cells casued dose-dependent mesenchymal-epithelial transition (MET)-like changes and impaired migration and invasion capabilities. In addition, CTAB reduced the levels of metastasis-related proteins including c-Met, phosphoinositide 3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), Twist, N-cadherin, and Vimentin. Moreover, pretreatment with hepatocyte growth factor (HGF) rescued CTAB-mediated effects. Conclusion: CTAB exhibited potent anti-EMT and anti-metastatic activities through the inhibition of migration and invasion of HA22T/VGH cells. CTAB interrupted the mesenchymal characteristics of HA22T/VGH cells, which were significantly alleviated by HGF in a dose-dependent manner. CTAB has the potential to evolve as a therapeutic agent for HCC.Liver cancer is the seventh most common malignancy worldwide (1). Furthermore, it is the fourth leading cause of cancer-related death in both sexes combined. This may be because disease progression could be asymptomatic in early and/or middle stages. After confirming a liver cancer diagnosis, standard therapy options include surgical excision, liver transplantation and molecular targeted therapy depending on patient's condition. However, recrudescence and adverse complications occur frequently because of high rates of metastasis and ineffectiveness of cancer treatments. For all these reasons it seems necessary to develop the novel chemical compounds without adverse effects for treating liver cancer.In general, the process of metastasis includes increase of cellular motility, the disruption of cellular interactions between adjacent cells, the extension of cell-matrix adhesion, and the degradation of the extracellular matrix (ECM) (3,4). Previous research has shown that epithelial-to-mesenchymal transition (EMT) is involved with cancer metastasis (3). During EMT epithelial cells acquire mesenchymal characteristics leading to increased migratory features, decreased epithelial cell 4513 *These Authors contributed equally to this study.

DHW-208, A Novel Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Has Anti-Hepatocellular Carcinoma Activity Through Promoting Apoptosis and Inhibiting Angiogenesis

“…After EMT, HCC cells lose their epithelial-like morphology, downregulate epithelial marker expression, and reduce intercellular adhesion ( 60 , 61 ). Then, HCC cells acquire mesenchymal cell morphology and upregulate the expression of mesenchymal markers, making them more prone to migration and invasion ( 61 , 62 ). Angiogenesis occurs frequently in tumors.…”

Cetyltrimethylammonium Bromide Disrupts Mesenchymal Characteristics of Human Tongue Squamous Cell Carcinoma SCC4 Cells Through Modulating Canonical TGF-β/Smad/miR-181b/TIMP3 Signaling Pathway

“…Approximately 50% confluent cells were pretreated with 1.0, 2.5, and 5.0 μM CTAB or vehicle control for 16 h at 37˚C, and then seeded in plates precoated with collagen type I (EMD Millipore, Billerica, MA, USA) for 1 h at 37˚C (16). After 8 h of incubation, the supernatant with unattached cells was discarded, and attached cells were quantified using the colorimetric WST-1 method.…”

Regulation on tumor metastasis by Raf kinase inhibitory protein

“…Moreover, deregulation of the receptors of these metastatic factors was closely associated with tumor progression. Among them, receptor tyrosine kinase (RTK) including c-Met [ 6 7 8 ], EGFR [ 7 9 ] and platelet-derived growth factor receptor-alpha [ 10 11 ] were frequently found to be overexpressed or mutated that activate various signaling cascades such as mitogen-activated protein kinase (MAPK) [ 4 12 13 14 15 ], NF-κB [ 16 ], AKT [ 17 18 ], STAT3 [ 19 20 ], NOTCH1 [ 21 ], and G protein-coupled receptor kinase 2 [ 22 ] leading to tumor progression. In the past decades, targeted therapy aiming at RTK and its downstream pathway for the prevention of tumor progression has been intensively studied.…”