Abstract
The thyromimetic agent GC-1 induces hepatocyte proliferation via Wnt/β-catenin signaling and may promote regeneration in both acute and chronic liver insufficiencies. However, β-catenin activation due to mutations in CTNNB1 is seen in a subset of hepatocellular carcinomas (HCC). Thus, it is critical to address any effect of GC-1 on HCC growth and development before its use can be advocated to stimulate regeneration in chronic liver diseases. In this study, we first examined the effect of GC-1 on β-catenin-T cell factor 4 activity in HCC cell lines harboring wild-type or mutated-CTNNB1. Next, we assessed the effect of GC-1 on HCC in FVB mice generated by hydrodynamic tail vein injection of hMet-S45Y-β-catenin, using the sleeping beauty transposon-transposase. Four weeks following injection, mice were fed 5 mg/kg GC-1 or basal diet for 10 or 21 days. GC-1 treatment showed no effect on β-catenin-T cell factor 4 activity in HCC cells, irrespective of CTNNB1 mutations. Treatment with GC-1 for 10 or 21 days led to a significant reduction in tumor burden, associated with decreased tumor cell proliferation and dramatic decreases in phospho-(p-)Met (Y1234/1235), p-extracellular signal-related kinase, and p-STAT3 without affecting β-catenin and its downstream targets. GC-1 exerts a notable antitumoral effect on hMet-S45Y-β-catenin HCC by inactivating Met signaling. GC-1 does not promote β-catenin activation in HCC. Thus, GC-1 may be safe for use in inducing regeneration during chronic hepatic insufficiency.
Highlights
IntroductionThyroid hormone 3,30-5-triiodo-L-thyronine (T3) is a strong regulator of multiple physiological processes, including cellular metabolic rate, embryonic development, and cell differentiation and proliferation.[1] In particular, T3 is a potent mitogen in mouse and rat liver, and increases liver regeneration following surgical hepatectomy and may be a useful agent to induce regeneration.[2] the use of T3 is hampered by its several side effects, such as increased heart rate, atrial arrhythmia, and muscle wasting.[3,4] many efforts have been made to design T3 analogs devoid of the toxic effects of T3 that could be used in the therapy of liverrelated disease
From the Departments of Pathology* and Medicinek and the Pittsburgh Liver Research Center,y University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; the Department of Biomedical Sciences,z University of Cagliari, Cagliari, Italy; the Department of Oncology,x Renmin Hospital of Wuhan University, Wuhan, China; and the Department of Radiation Oncology,{ Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Science, Jinan, China
We demonstrate that GC-1 decreases tumor burden owing to decreased tumor cell proliferation with a notable decrease in Meteextracellular signal-related kinase (Erk) and Met-Stat[3] signaling and no effect on Akt or Wnt/b-catenin signaling
Summary
Thyroid hormone 3,30-5-triiodo-L-thyronine (T3) is a strong regulator of multiple physiological processes, including cellular metabolic rate, embryonic development, and cell differentiation and proliferation.[1] In particular, T3 is a potent mitogen in mouse and rat liver, and increases liver regeneration following surgical hepatectomy and may be a useful agent to induce regeneration.[2] the use of T3 is hampered by its several side effects, such as increased heart rate, atrial arrhythmia, and muscle wasting.[3,4] many efforts have been made to design T3 analogs devoid of the toxic effects of T3 that could be used in the therapy of liverrelated disease In this scenario, the thyromimetic GC-1 (sobetirome) may be a promising option. Previous studies have shown that hepatocyte proliferation induced by T3/GC-1 is mostly due to their
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