RESUMO
Sorafenib, a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), has been shown to be a potent ferroptosis inducer in HCC. However, we found that there was a lower level of ferroptosis in sorafenib-resistant HCC samples than in sorafenib-sensitive HCC samples, suggesting that sorafenib resistance in HCC may be a result of ferroptosis suppression. Recent reports have shown that long noncoding RNAs (lncRNAs) are involved in programmed cell death (PCD), including apoptosis and ferroptosis. This study aimed to investigate the roles and underlying molecular mechanisms of lncRNAs in sorafenib-induced ferroptosis in HCC cells. Using lncRNA sequencing, we identified a ferroptosis-related lncRNA, URB1-antisense RNA 1 (AS1), which was highly expressed in sorafenib-resistant HCC samples and predicted poor survival in HCC. Furthermore, URB1-AS1 mitigates sorafenib-induced ferroptosis by inducing ferritin phase separation and reducing the cellular free iron content. Hypoxia inducible factor (HIF)-1α was identified as a key factor promoting URB1-AS1 expression in sorafenib-resistant HCC cells. Notably, we found that specifically inhibiting the expression of URB1-AS1 with N-acetylgalactosamine (GalNAc)-small interfering (si)URB1-AS1 successfully enhanced the sensitivity of HCC cells to sorafenib in an in vivo tumor model. Our study uncovered a critical role for URB1-AS1 in the repression of ferroptosis, suggesting URB1-AS1 targeting may represent a potential approach to overcome sorafenib resistance in HCC.
Assuntos
Carcinoma Hepatocelular , Ferroptose , Neoplasias Hepáticas , MicroRNAs , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Sorafenibe/farmacologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , RNA Antissenso , Ferritinas/metabolismo , MicroRNAs/genética , Linhagem Celular Tumoral , RNA Interferente Pequeno/genética , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genéticaRESUMO
The liver plays central roles in coordinating different metabolic processes, such as the catabolism of amino acids. In this study, we identify a loss of tyrosine catabolism and a concomitant increase in serum tyrosine levels during liver cancer development. Liver cells with disordered tyrosine catabolism, as exemplified by the suppression of a tyrosine catabolic enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), display augmented tumorigenic and proliferative potentials. Metabolomics profiling and isotope tracing reveal the metabolic reliance of HPD-silenced cells on glutamine, coupled with increased tricarboxylic acid cycle metabolites and their associated amino acid pools. Mechanistically, HPD silencing reduces ketone bodies, which regulate the proliferative and metabolic phenotypes via the AMPK/mTOR/p70S6 kinase pathway and mTOR-dependent glutaminase (GLS) activation. Collectively, our results demonstrate a metabolic link between tyrosine and glutamine metabolism, which could be exploited as a potentially promising anticancer therapy for liver cancer.