Abstract
Hepatocellular carcinoma (HCC), a hepatic malignancy, has a poor prognosis and contributes to cancer-related death worldwide. Cellular senescence is an anticancer therapeutic strategy that causes irreversible cell cycle arrest and enables immune-mediated clearance of cancer cells. Atorvastatin, an HMG-CoA reductase inhibitor, has been shown to inhibit tumor growth and induce apoptosis or autophagy in malignant tumors. However, whether atorvastatin can induce HCC cell senescence and the mechanisms involved are poorly understood. The effects of atorvastatin-induced senescence were examined in both HCC cells and mouse xenograft models. The phenomenon and mechanism of senescence were examined by cell cycle analysis, senescence-associated β-galactosidase (SA-β-gal) staining and western blotting in HCC cells, and HCC tissues from mice were analyzed by immunohistochemical (IHC) staining. We demonstrated that atorvastatin induced cell growth inhibition and G0/G1 phase cell cycle arrest, leading to senescence in HCC cells. Atorvastatin-induced senescence was independent of p53, p14, and p16, and atorvastatin not only decreased the secretion of IL-6, a major senescence-associated secretory phenotype (SASP) factor, and the phosphorylation of STAT3 but also inhibited the expression of hTERT, a catalytic subunit of telomerase. Supplementation with exogenous IL-6 reversed both atorvastatin-induced suppression of STAT3 phosphorylation and hTERT expression and atorvastatin-induced senescence. Overexpression of constitutively activated STAT3 rescued HCC cells from atorvastatin-induced hTERT suppression and senescence. Moreover, atorvastatin decreased tumor growth in mouse xenograft models. Consistent with these results, atorvastatin decreased the IL-6, p-STAT3, and hTERT levels and increased β-gal expression in tumor sections. Taken together, these data indicate that atorvastatin can induce atypical cellular senescence in HCC cells to inhibit tumor growth, an effect mediated by downregulation of hTERT through suppression of the IL-6/STAT3 pathway.
Highlights
Hepatocellular carcinoma (HCC) is the most common malignant liver cancer with a poor prognosis and is responsible for many cancer-related deaths worldwide[1,2]
We demonstrated that the involvement of interleukin (IL)-6 in atorvastatin-induced cellular senescence was mediated by the regulation of hTERT through the IL-6/STAT3 signaling pathway
The results indicated that the low dose of atorvastatin reduced the growth rate and caused G0/G1 arrest in HCC cells
Summary
Hepatocellular carcinoma (HCC) is the most common malignant liver cancer with a poor prognosis and is responsible for many cancer-related deaths worldwide[1,2]. The most important risk factor for HCC progression is long-term chronic liver inflammation, Official journal of the Cell Death Differentiation Association. Wang et al Cell Death Discovery (2020)6:17 which causes liver damage; this damage greatly contributes to HCC development. Cellular senescence is an important factor that restricts tumor growth and modulates cancer-associated immune responses. Cellular senescence is a state of irreversible cell cycle arrest in response to stress conditions, such as DNA damage, telomere dysfunction, chromatin disruption, and oncogene activation[4,5]. Senescent cells display the senescence-associated secretory phenotype (SASP), which corresponds to the secretion of various cytokines, chemokines, growth factors, and proteases that affect the surrounding cells; the SASP has been reported to have antitumorigenic effects[9,10]. The induction of senescence in cancer cells has been suggested as a therapeutic strategy
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