Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Betel-quid use is associated with liver cancer whereas its constituent arecoline is cytotoxic, genotoxic, and induces p53-dependent p21(WAF1) protein expression in Clone-9 cells (rat hepatocytes). The ataxia telangiectasia mutated (ATM)/rad3-related (ATR)-p53-p21(WAF1) and the phosphatidylinositol-3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathways are involved in the DNA damage response and the pathogenesis of cancers. Thus, we studied the role of ATM/ATR and PI3K in arecoline-induced p53 and p21(WAF1) protein expression in Clone-9 cells. We found that arecoline (0.5 mM) activated the ATM/ATR kinase at 30 min. The arecoline-activated ATM/ATR substrate contained p-p53Ser15. Moreover, arecoline only increased the levels of the p-p53Ser6, p-p53Ser15, and p-p53Ser392 phosphorylated p53 isoforms among the known isoforms. ATM shRNA attenuated arecoline-induced p-p53Ser15 and p21(WAF1) at 24 h. Arecoline (0.5 mM) increased phosphorylation levels of p-AktSer473 and p-mTORSer2448 at 30-60 min. Dominant-negative PI3K plasmids attenuated arecoline-induced p21(WAF1), but not p-p53Ser15, at 24 h. Rapamycin attenuated arecoline-induced phosphrylated p-p53Ser15, but not p21(WAF1), at 24 h. ATM shRNA, but not dominant-negative PI3K plasmids, attenuated arecoline-induced p21(WAF1) gene transcription. We conclude that arecoline activates the ATM/ATR-p53-p21(WAF1) and the PI3K/Akt-mTOR-p53 pathways in Clone-9 cells. Arecoline-induced phosphorylated p-p53Ser15 expression is dependent on ATM whereas arecoline-induced p21(WAF1) protein expression is dependent on ATM and PI3K. Moreover, p21(WAF1) gene is transcriptionally induced by arecoline-activated ATM.
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PMID:Arecoline-induced phosphorylated p53 and p21(WAF1) protein expression is dependent on ATM/ATR and phosphatidylinositol-3-kinase in clone-9 cells. 1934 84

Arecoline can be used to treat diseases including glaucoma and tapeworm infection, however, long-term administration can cause severe adverse effects, including oral submucosal fibrosis, oral cancer, hepatic injury and liver cancer. Autophagy serves a role in these injuries. The present study established a mouse model of arecoline-induced hepatic injury and investigated the role of autophagy-associated proteins in this injury. The results indicated that the expression levels of the autophagy marker protein microtubule associated protein 1 light chain 3 B (MAP1LC3B) and autophagy-promoting protein beclin 1 were elevated in the injured hepatic cells, while the expression levels of a well-known negative regulator of autophagy, mammalian target of rapamycin (mTOR), were reduced. Following treatment of the hepatic injury with glutathione, the liver function improved and liver damage was reduced effectively. Compared with the control group, the expression levels of both MAP1LC3B and beclin 1 were significantly upregulated in the glutathione-treated mice, but the expression of mTOR was significantly downregulated. It may be concluded that in the process of protecting against arecoline-induced hepatic injury, glutathione cooperates with mTOR and beclin 1 to accelerate autophagy, maintaining stable cell morphology and cellular functions.
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PMID:Effect of autophagy-associated proteins on the arecoline-induced liver injury in mice. 3021 23