p53-p66(shc)/miR-21-Sod2 signaling is critical for the inhibitory effect of betulinic acid on hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third cause of cancer-related death. Betulinic acid (BA) is a pentacyclic triterpene, possessing potential pro-apoptotic activities. The present study was designed to evaluate the effect of BA on tumor growth in mice and HCC cell proliferation in vitro. We found that BA dose-dependently inhibited tumor growth in mice induced by DEN plus CCl4 (D/C) and suppressed cell viability and proliferation in several HCC cell lines. In addition, BA increased mitochondrial ROS generation and mitochondrial dysfunction, activating molecular apoptotic events and leading to apoptotic cell death. p53 was increased by BA in D/C-treated mice and HCC cells and inhibition of p53 significantly suppressed the pro-apoptotic and anti-tumor effect of BA. Increase of p66(shc) was involved in the pro-apoptotic and anti-tumor effect of BA. Moreover, BA-induced increase of p66(shc) was dependent upon p53. Sod2 expression was reduced by BA treatment, and a Sod2 mimic (MnTBAP) significantly blocked the pro-apoptotic and anti-tumor effect of BA. Furthermore, miR-21 was increased by BA in D/C-treated mice and HCC cells and inhibition of miR-21 significantly suppressed the pro-apoptotic effect of BA. miR-21 inhibitor attenuated BA-induced decrease of Sod2 and p53 inhibitor blocked BA-induced increase of miR-21. These results demonstrated that p53 is responsible for the anti-tumor effect of BA through up-regulation of p66(shc) and miR-21 and down-regulation of Sod2 expression, leading to mitochondrial ROS accumulation and apoptosis. The p53-p66(shc)/miR-21-Sod2 signaling is critical for BA-inhibited tumor growth and cancer cell proliferation.

• Authors: Jingyue Yang, Bo Qiu, Xiao Li, Hongmei Zhang, Wenchao Liu
• Journal: Toxicology letters (Toxicol Lett) Vol. 238 Issue 3 Pg. 1-10 (Nov 04 2015) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 26222667 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• MIRN21 microRNA, mouse
• MicroRNAs
• Pentacyclic Triterpenes
• Shc Signaling Adaptor Proteins
• Shc1 protein, mouse
• Src Homology 2 Domain-Containing, Transforming Protein 1
• Triterpenes
• Tumor Suppressor Protein p53
• Diethylnitrosamine
• Carbon Tetrachloride
• Superoxide Dismutase
• superoxide dismutase 2
• Betulinic Acid

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
• Carbon Tetrachloride (toxicity)
• Carcinoma, Hepatocellular (chemically induced, drug therapy, prevention & control)
• Cell Line, Tumor
• Cell Survival
• Diethylnitrosamine (toxicity)
• Dose-Response Relationship, Drug
• Gene Expression Regulation
• Humans
• Liver Neoplasms (chemically induced, drug therapy, prevention & control)
• Mice
• MicroRNAs (genetics, metabolism)
• Pentacyclic Triterpenes
• Random Allocation
• Shc Signaling Adaptor Proteins (genetics, metabolism)
• Signal Transduction
• Src Homology 2 Domain-Containing, Transforming Protein 1
• Superoxide Dismutase (genetics, metabolism)
• Triterpenes (pharmacology, therapeutic use)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Betulinic Acid