Abstract
Hepatocellular carcinoma (HCC) is a malignant type of primary liver cancer with high incidence and mortality, worldwide. A major challenge in the treatment of HCC is chemotherapeutic resistance. It is therefore necessary to develop novel anticancer drugs for suppressing the growth of HCC cells and overcoming drug resistance for improving the treatment of HCC. Violacein is a deep violet-colored indole derivative that is produced by several bacterial strains, including Chromobacterium violaceum, and it possesses numerous pharmacological properties, including antitumor activity. However, the therapeutic effects of violacein and the mechanism underlying its antitumor effect against HCC remain to be elucidated. This study is the first to demonstrate that violacein inhibits the proliferation and stemness of Huh7 and Hep3B HCC cells. The antiproliferative effect of violacein was attributed to cell cycle arrest at the sub-G1 phase and the induction of apoptotic cell death. Violacein induced nuclear condensation, dissipated mitochondrial membrane potential (MMP), increased generation of reactive oxygen species (ROS), activated the caspase cascade, and upregulated p53 and p21. The anticancer effect of violacein on HCC cells was also associated with the downregulation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)1/2 signaling. Violacein not only suppressed the proliferation and formation of tumorspheres of Huh7 and Hep3B cancer stem-like cells but also reduced the expression of key markers of cancer stemness, including CD133, Sox2, Oct4, and Nanog, by inhibiting the signal transducer and activator of transcription 3 (STAT3)/AKT/ERK pathways. These results suggest the therapeutic potential of violacein in effectively suppressing HCC by targeting the proliferation and stemness of HCC cells.
Highlights
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, and it accounts for approximately 75% of all cases of liver cancer [1]
Instudy orderdemonstrate to examine whether violacein affectsinhibited the proliferation of HCCof cells, Huh7 of our that violacein effectively the proliferation cells cells were treated with violacein at various concentrations
In order to further explore the role of apoptosis in the inhibitory effect of violacein on the proliferation of HCC cells, we investigated the effect of violacein on the progression of the cell cycle in Huh7 cells by flow cytometric analysis
Summary
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, and it accounts for approximately 75% of all cases of liver cancer [1]. In 2018, HCC was the seventh most prevalent cancer worldwide and the second most common cause of cancer-related mortality [2]. The incidence of HCC is high in Asia and Africa [3]. The primary causes of HCC include chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infections, alcoholic cirrhosis, and non-alcoholic steatohepatitis (NASH) [4]. The early diagnosis and effective treatment of HCC continues to be a challenge. Most patients are asymptomatic and develop symptoms at an advanced stage of the disease
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