Abstract
The aim of the present study was to verify the effects of fluoxetine on dysregulation of apoptosis and invasive potential in human hepatocellular carcinoma (HCC) SK-Hep1 and Hep3B cells. Cells were treated with different concentrations of fluoxetine for different times. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assays were used for testing the effects of fluoxetine on cell viability. The regulation of apoptosis signaling, and anti-apoptotic, proliferation, and metastasis-associated proteins after fluoxetine treatment were assayed by flow cytometry and Western blotting assay. The detection of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation after fluoxetine treatment was performed by NF-κB reporter gene assay. The results demonstrated that fluoxetine significantly reduced cell viability, cell migration/invasion, NF-κB, extracellular signal-regulated kinases (ERK) activation, and expression of anti-apoptotic (Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (C-FLIP), Myeloid cell leukemia-1 (MCL-1), X-Linked inhibitor of apoptosis protein (XAIP), and Survivin), proliferation (Cyclin-D1), angiogenesis (vascular endothelial growth factor (VEGF)), and metastasis-associated proteins (matrix metalloproteinase-9 (MMP-9)). Fluoxetine also significantly induced apoptosis, unregulated extrinsic (activation of first apoptosis signal protein and ligand (Fas/FasL), and caspase-8) and intrinsic (loss of mitochondrial membrane potential (ΔΨm) pathways and increased Bcl-2 homologous antagonist killer (BAK) apoptosis signaling. Taken together, these results demonstrated that fluoxetine induced apoptosis through extrinsic/intrinsic pathways and diminished ERK/NF-κB-modulated anti-apoptotic and invasive potential in HCC cells in vitro.
Highlights
Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is the second leading cause of cancer-related death worldwide [1]
The results indicated that fluoxetine significantly decreased the quantity of viable cells (Figure 1A)
Cell viability was inhibited by 50–60% as compared to the control group at 48 h after 30 μM and 40 μM fluoxetine treatment
Summary
Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is the second leading cause of cancer-related death worldwide [1]. Sorafenib and regorafenib are oral multi-kinase inhibitors which promote apoptosis and suppress anti-apoptotic and metastatic activity and are approved for treatment of HCC [4,5]. Induction of apoptosis and inhibition of anti-apoptotic and metastatic activity may be an available treatment strategy for patients with HCC. Antidepressants modulate inhibition of tumor growth through triggering antitumor immunity, inducing apoptosis, and blocking intracellular signaling transduction [9,10]. Many antidepressants such as desipramine, sertraline, and fluoxetine, have been shown to induce apoptosis in HCC [11,12,13]
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