Curcumin regulates cell fate and metabolism by inhibiting hedgehog signaling in hepatic stellate cells

Abstract

Accumulating evidence indicates that Hedgehog (Hh) signaling becomes activated in chronic liver injury and plays a role in the pathogenesis of hepatic fibrosis. Hepatic stellate cells (HSCs) are Hh-responsive cells and activation of the Hh pathway promotes transdifferentiation of HSCs into myofibroblasts. Targeting Hh signaling may be a novel therapeutic strategy for treatment of liver fibrosis. We previously reported that curcumin has potent antifibrotic effects in vivo and in vitro, but the underlying mechanisms are not fully elucidated. This study shows that curcumin downregulated Patched and Smoothened, two key elements in Hh signaling, but restored Hhip expression in rat liver with carbon tetrachlorideinduced fibrosis and in cultured HSCs. Curcumin also halted the nuclear translocation, DNA binding, and transcription activity of Gli1. Moreover, the Hh signaling inhibitor cyclopamine, like curcumin, arrested the cell cycle, induced mitochondrial apoptosis, reduced fibrotic gene expression, restored lipid accumulation, and inhibited invasion and migration in HSCs. However, curcumin's effects on cell fate and fibrogenic properties of HSCs were abolished by the Hh pathway agonist SAG. Furthermore, curcumin and cyclopamine decreased intracellular levels of adenosine triphosphate and lactate, and inhibited the expression and/or function of several key molecules controlling glycolysis. However, SAG abrogated the curcumin effects on these parameters of glycolysis. Animal data also showed that curcumin downregulated glycolysis-regulatory proteins in rat fibrotic liver. These aggregated data therefore indicate that curcumin modulated cell fate and metabolism by disrupting the Hh pathway in HSCs, providing novel molecular insights into curcumin reduction of HSC activation.

Tetramethylpyrazine attenuates sinusoidal angiogenesis via inhibition of hedgehog signaling in liver fibrosis

“…Accumulating evidence suggested that hedgehog signaling played a pivotal role in regulating critical cell fate decisions and was involved in wound‐healing responses in a number of adult tissues, including the liver . Previous studies, including ours, have shown that hedgehog signaling promoted proliferation and inhibited apoptosis in HSCs, also accelerated liver fibrosis and hepatocarcinogenesis . Interestingly, the most relevant studies demonstrated that hedgehog signaling was overactivated during LSEC capillarization and played a crucial role in this process controlling this process in cultured LSECs .…”

“…These findings demonstrated that hedgehog signaling was one of the most important factors that control angiogenesis. Our previous study demonstrated that curcumin regulated cell fate and metabolism by inhibiting hedgehog signaling in HSCs . However, the potential mechanisms of hedgehog pathway activation and influence of the phenotype of liver sinusoidal endothelial cells (LSECs) were quite limited.…”

Naturally occurring compounds acting as potent anti‐metastatic agents and their suppressing effects on Hedgehog and WNT/β‐catenin signalling pathways

“…Curcumin can also modulate Bcl2 protein family and caspase cascade activation in dependence to Hh signalling pathway blockade. Curcumin can also result in G0/G1 cell cycle arrest and induce Bcl2‐mediated apoptosis again by pharmacological blockade of Hedgehog pathway in HSC cell lines . In a study with the purpose of determining whether osteosarcoma progression can be disrupted by inhibition of Wnt/β‐catenin pathway through curcumin consumption or not, it was demonstrated that curcumin could suppress intrinsic and activated β‐catenin/TCF transcriptional activities and its nuclear concentration was drastically decreased.…”

“…The efficacy of curcumin in several cancers has been well studied and reported in literature. 109 Curcumin administration has shown to result in signifi- 111 In a study with the purpose of determining whether osteosarcoma progression can be disrupted by inhibition of Wnt/β-catenin pathway through curcumin consumption or not, it was demonstrated that curcumin could suppress intrinsic and activated β-catenin/TCF transcriptional activities and its nuclear concentration was drastically decreased. Another mechanism was proposed to be inhibition of osteosarcoma invasiveness by downregulation of Wnt/β-catenin and matrix metalloproteinases (MMP)-9, cyclin D1, c-Myc and survivin.…”

Curcumin increases efficiency of γ-irradiation in gliomas by inhibiting Hedgehog signaling pathway

“…Curcumin was used as an inhibitor to Hedgehog signaling pathway. 47,48 In some other research, 20-40 mM dose of Curcumin is used as a approperate dose for inhibiting EMT. 49,50 According to other research and our prior work, 20 mM Curcumin acted for 24 hours was used as a treatment in vitro, and 60 mg/kg/d was the dose used for intraperitoneal injection in vivo.…”