isoliensinine and Carcinoma--Hepatocellular

Our previous study discovered that isoliensinine (isolie) triggers hepatocellular carcinoma (HCC) cell apoptosis via inducing p65 dephosphorylation at Ser536 and inhibition of NF-κB. Here, we showed that isolie promoted p65/PP2A interaction in vitro and in vivo. Repression of PP2A activity or knockdown of the expression of PP2A-C (the catalytic subunit of PP2A) abrogated isolie-provoked p65 dephosphorylation. I2PP2A is an endogenous PP2A inhibitor. Isolie directly impaired PP2A/I2PP2A interaction. Knockdown of I2PP2A boosted p65/PP2A association and p65 dephosphorylation. Overexpression of I2PP2A restrained isolie-induced p65 dephosphorylation. Untransformed hepatocytes were insensitive to isolie-induced NF-κB inhibition and cell apoptosis. In these cells, basal levels of I2PP2A and p65 phosphorylation at Ser536 were lower than in HCC cells. These findings collectively indicated that isolie suppresses NF-κB in HCC cells through impairing PP2A/I2PP2A interaction and stimulating PP2A-dependent p65 dephosphorylation at Ser536.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Catalytic Domain; DNA-Binding Proteins; Hep G2 Cells; Hepatocytes; Histone Chaperones; Humans; Isoquinolines; Liver Neoplasms; Male; Mice; Mice, Nude; Phosphorylation; Protein Phosphatase 2; Recombinant Proteins; Serine; Transcription Factor RelA; Transcription Factors

Isoliensinine (isolie) is an alkaloid produced by the edible plant Nelumbo nucifera. Here, we unveiled that isolie was able to provoke HepG2, Huh-7, and H22 hepatocellular carcinoma (HCC) cell apoptosis. Isolie decreased NF-κB activity and constitutive phosphorylation of NF-κB p65 subunit at Ser536 in HCC cells. Overexpression of p65 Ser536 phosphorylation mimics abrogated isolie-mediated HCC cell apoptosis. Furthermore, intraperitoneal injection of isolie inhibited the growth of Huh-7 xenografts in nude mice. Additionally, isolie given by both intraperitoneal injection and gavage diminished the proliferation of transplanted H22 cells in Kunming mice. Reduced tumor growth in vivo was associated with inhibited p65 phosphorylation at Ser536 and declined NF-κB activity in tumor tissues. Finally, we revealed that isolie was bioavailable in the blood of mice and exhibited no detectable toxic effects on tumor-bearing mice. Our data provided strong evidence for the anti-HCC effect of isolie.

Topics: Alkaloids; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Isoquinolines; Liver Neoplasms; Male; Mice; Mice, Nude; Molecular Structure; Nelumbo; NF-kappa B; Plant Extracts; Signal Transduction