Targeting p53/TRAIL/caspase-8 signaling by adiponectin reverses thioacetamide-induced hepatocellular carcinoma in rats

• Published in: Environmental toxicology and pharmacology 2019-11, Vol.72, p.103240, Article 103240
• Main Authors: Nazmy, Entsar A., El-Khouly, Omar A., Zaki, Marwa M.A., Elsherbiny, Nehal M., Said, Eman, Al-Gayyar, Mohammed M.H., Salem, Hatem A.
• Format: Article
• Language: English
• Subjects: Activation; Adiponectin; Adiponectin - pharmacology; Adiponectin - therapeutic use; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Apoptosis; c-JNK; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Caspase 8 - metabolism; Caspase-3; Caspase-8; Cirrhosis; HCC; Hepatocellular carcinoma; Impact analysis; Liver - drug effects; Liver - pathology; Liver cirrhosis; Liver Neoplasms - chemically induced; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Nodules; p53; p53 Protein; Quality of life; Rats, Sprague-Dawley; Reduction; Restoration; Serum levels; Signal Transduction - drug effects; Signaling; Thioacetamide; TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; α-Fetoprotein
• ISSN: 1382-6689; 1872-7077
• DOI: 10.1016/j.etap.2019.103240

[Display omitted] •Adiponectin is a multimeric proteins secreted from the white adipose tissue.•Adiponectin possesses antitumor activity against HCC.•Adiponectin blocked HCC-induced reduction in p53 and TRAIL.•Adiponectin ameliorated HCC-induced activation of c-JNK.•Adiponectin activated the apoptotic pathway. Given the enormous impact of HCC on the patients' quality of life and healthcare economics, the current study was conducted to investigate the potential ability of adiponectin to reverse established HCC and to investigate the underlying mechanisms which control the chemotherapeutic and hepatoprotective effects. HCC was induced in Male Sprague Dawely rats by I.P. injection of thioacetamide(200 mg/kg) 3 times/week for 14 weeks.HCC development was confirmed by histopathological examination and assessment of serum levels of α-fetoprotein (AFP). Adiponectin was administered (5 μg/kg, I.P.) starting from week 13 of the experiment and for further 4 weeks. Adiponectinadministration revealed a significant antitumor activity with significant improvement in liver functions and oxidative status. Nevertheless, pathological features as cirrhosis, dysplastic changes, and tumoral nodules were significantly attenuated with significant enhancement in hepatic caspase-3 immunostaining. Mechanistically, adiponectin administration was associated with significant restoration of p53 activity; which increased by 133%, with a reduction in HCC-induced expression of-JNK which decreased by 53%as well as a significant enhancement of hepatic TRAIL and caspase-8 activities which increased by 27% and 20% respectively. In conclusion; Adiponectin can be proposed as a promising therapy for HCC. Adiponectin's tumoricidal activity can be partially mediated by blocking HCC-induced reduction in p53 expression as well as reactivation of TRAIL signaling and induction of apoptotic pathway providing more protection for the body against the tumor.