RESUMO
Traditionally, musk has been used as an analgesic to treat pain associated with cancer. Hepatocellular carcinoma (HCC) is an aggressive tumor; however, patients with liver cancer that received musk were reported to live longer and have a higher quality of life. Thus, the present study aimed to investigate whether muscone, a macrocyclic compound of musk, demonstrated potential as an antiliver cancer drug for the nonsurgical treatment of advanced liver cancer. Briefly, liver cancer cells were treated with muscone and the rates of cellular apoptosis and autophagy were investigated using staining techniques and western blotting. The underlying molecular mechanisms of muscone were evaluated using highthroughput sequencing and the in vitro effects of muscone were subsequently validated in vivo using a nude mouse model. Muscone increased the rates of apoptosis and autophagy in liver cancer cells; the increase in cellular apoptosis was observed to occur through endoplasmic reticulum stress responses, whereas musconeinduced autophagy was closely associated with the AMP kinase/mTOR complex 1 signaling pathway. These findings were verified in vivo. Notably, sestrin2 expression levels were also significantly decreased in liver cancer tissues compared with paracancerous tissues. In conclusion, the present study suggests that muscone demonstrates potential as an anticancer drug, and the findings of the present study provide the basis for the development of effective anticancer drugs derived from natural compounds.
Assuntos
Adenilato Quinase/genética , Carcinoma Hepatocelular/tratamento farmacológico , Cicloparafinas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Nucleares/genética , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Cicloparafinas/química , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , CamundongosRESUMO
Ferroptosis is a non-apoptotic, iron-dependent oxidative form of cell death that is specifically induced by erastin in RAS mutant cancer cells. Ferroptotic cell death is the result of membrane lipid peroxide damage caused by the accumulation of hydroxyl radicals derived from H2O2 by the Fenton reaction. Peroxidases are key cellular antioxidant enzymes that block such damaging processes. Few studies have examined the roles of long non-coding RNAs (lncRNAs) in the regulation of cellular oxidative stress, especially in ferroptosis. Here, we demonstrated that erastin upregulated the lncRNA GABPB1-AS1, which downregulated GABPB1 protein levels by blocking GABPB1 translation, leading to the downregulation of the gene encoding Peroxiredoxin-5 (PRDX5) peroxidase and the eventual suppression of the cellular antioxidant capacity. Such effects critically inhibited the cellular antioxidant capacity and cell viability. Additionally, high expression levels of GABPB1 were correlated with poor prognosis of hepatocellular carcinoma (HCC) Patients, while high GABPB1-AS1 levels in HCC patients correlated with improved overall survival. Collectively, these data demonstrate a mechanistic link between GABPB1 and its antisense lncRNA GABPB1-AS1 in erastin-induced ferroptosis and establish GABPB1 and GABPB1-AS1 as attractive therapeutic targets for HCC.
