All-trans retinoic acid inhibits the malignant behaviors of hepatocarcinoma cells by regulating ferroptosis

Wan

The Journal of Gene Medicine

et al. 2023

BackgroundThe involvement of ferroptosis has been found in many pathological conditions of the lung. The genetic engineering of ferroptosis‐related genes may provide a potential target for the treatment of lung adenocarcinoma (LUAD).MethodsNine ferroptosis regulators and markers were collected from FerrDb and their somatic mutations and expressions were analyzed based on The Cancer Genome Atlas (TCGA)‐LUAD cohort data. Least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were performed to screen genes significantly associated with ferroptosis. The ferroptosis‐related gene signature was constructed using TCGA‐LUAD cohort data and was verified using the GSE cohort with pooled data for GSE30219, GSE31210, GSE37745 and GSE50081. Immune microenvironment component and mutation analysis were performed for genes in the ferroptosis‐related gene signature.ResultsAll nine ferroptosis regulators and markers were differentially expressed between normal LUAD tumor tissues and adjacent normal tissues and were related to copy number variation. The expression of 1329 genes were significantly associated with nine ferroptosis regulators and markers in the TCGA‐LUAD dataset, five (ALDOA, PLK1, CD47, CENPC and TMOD3) of which were integrated into a ferroptosis‐related gene signature to calculate the risk score of LUAD samples, showing a significant correlation with the abundance of immune cell infiltration and the immune score. Molecular docking showed the binding activity of natural active compound quercetin to target proteins ALDOA and CD47, as well as the binding activity of aristolochic acid to PLK1 protein and TMOD3 protein.ConclusionsIn the present study, a ferroptosis‐related gene signature with predictive value for LUAD prognosis was constructed, in which the gene was a potential therapeutic target for LUAD. Quercetin and aristolochic acid were potential candidates for inhibiting these targets by directly binding to them and showing high affinity and strong stability.

Section: Discussionmentioning

confidence: 99%

“…The influence of ferroptosis on cancer has received considerable attention in recent years 28,29 . Tumor suppressors such as BAP1 and p53 control the activation of ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

New molecular insights into ferroptosis in lung adenocarcinoma progression and pharmacological compounds for targeted therapy

Wan

The Journal of Gene Medicine

et al. 2023

“…Conversely, ATRA treatment has been reported to increase the expression of the OTUD7B gene, an NF-κB inhibitory factor [47], indicating that inflammatory cell death, as observed with GGA or PA treatment, is unlikely to occur. ATRA has been shown to induce apoptotic cell death in human HCC cell lines PLC/PRF/5 and HLE [48], and ferroptosis cell death in HepG2 and Hep3B cells [49]. However, there are also reports suggesting that ATRA inhibits ferroptosis in neuronal cell lines [50].…”

Section: Mode Of Regulated Cell Deathmentioning

confidence: 99%

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

Shidoji

2024

Preprint

Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all-trans retinoic acid (ATRA). Mechanistic studies reveal GGA's unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA's potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA's anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.

“…Ferroptosis is a form of programmed cell death triggered by excessive iron accumulation. Sun et al 81 detected differentially expressed genes between HCC and normal liver tissues, revealing 53 genes associated with ferroptosis. Treating HCC cells with ATRA downregulated the majority of genes related to ferroptosis.…”

Section: Ra and Liver Tumorsmentioning

confidence: 99%

Retinoic acids and nuclear receptor signaling in liver development: Pathogenic roles in liver diseases

Jia,

2023

Pediatric Discovery

Self Cite

Retinoic acid (RA) serves as a metabolic intermediate of vitamin A. It plays a crucial physiological role in regulating cell proliferation, differentiation, apoptosis, embryonic development, and immunomodulation. Once vitamin A enters the body in the form of retinol, it undergoes conversion into RA through the intestinal epithelium and liver. Subsequently, it interacts with retinoic acid receptors and retinoid X receptors within the cell nucleus, thereby regulating gene expression. Throughout liver development, RA exerts precise temporal control, stimulating liver growth, inducing RALDH2 expression in liver somatic epithelial cells, and influencing hepatocyte differentiation. Recent studies have consistently demonstrated the indispensable connection between RA deficiency and the development of liver diseases, including nonalcoholic fatty liver disease, chronic hepatitis, liver fibrosis, and liver tumors. Studying the mechanisms underlying the relationship between RA and disease can enhance our understanding and improve disease treatment. This paper provides a comprehensive review of the role of RA signaling in liver development and liver diseases.