Suppressing activity of tributyrin on hepatocarcinogenesis is associated with inhibiting the p53-CRM1 interaction and changing the cellular compartmentalization of p53 protein
| Autor: | Frederick A. Beland, Maria Aderuza Horst, Paulo Eduardo Latorre Martins Tavares, Laura Helena Gasparini Fernandes, Fernando Salvador Moreno, Svitlana Shpyleva, Igor P. Pogribny, Marta Pogribna, Aline de Conti, Kelly Silva Furtado, Volodymyr Tryndyak, Juliana Festa Ortega, Renato Heidor |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Cytoplasm tributyrin Carcinoma Hepatocellular Tributyrin Receptors Cytoplasmic and Nuclear Apoptosis Biology Karyopherins Bioinformatics CRM1 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans chemoprevention Rats Wistar CARCINOMA HEPATOCELULAR Triglycerides Cell Proliferation Cell Nucleus p53 subcellular localization Cell growth Liver Neoplasms hepatocarcinogenesis Cancer Sodium butyrate medicine.disease Cell Compartmentation Gene Expression Regulation Neoplastic Disease Models Animal 030104 developmental biology Oncology chemistry Cell culture 030220 oncology & carcinogenesis Cancer research Butyric Acid Apoptotic signaling pathway Tumor Suppressor Protein p53 Liver cancer Protein Binding Research Paper |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP Oncotarget |
| Popis: | Hepatocellular carcinoma (HCC), an aggressive and the fastest growing life-threatening cancer worldwide, is often diagnosed at intermediate or advanced stages of the disease, which substantially limits therapeutic approaches for its successful treatment. This indicates that the prevention of hepatocarcinogenesis is probably the most promising approach to reduce both the HCC incidence and cancer-related mortality. In previous studies, we demonstrated a potent chemopreventive effect of tributyrin, a butyric acid prodrug, on experimental hepatocarcinogenesis. The cancer-inhibitory effect of tributyrin was linked to the suppression of sustained cell proliferation and induction of apoptotic cell death driven by an activation of the p53 apoptotic signaling pathway. The goal of the present study was to investigate the underlying molecular mechanisms linked to tributyrin-mediated p53 activation. Using in vivo and in vitro models of liver cancer, we demonstrate that an increase in the level of p53 protein in nuclei, a decrease in the level of cytoplasmic p53, and, consequently, an increase in the ratio of nuclear/cytoplasmic p53 in rat preneoplastic livers and in rat and human HCC cell lines caused by tributyrin or sodium butyrate treatments was associated with a marked increase in the level of nuclear chromosome region maintenance 1 (CRM1) protein. Mechanistically, the increase in the level of nuclear p53 protein was associated with a substantially reduced binding interaction between CRM1 and p53. The results demonstrate that the cancer-inhibitory activity of sodium butyrate and its derivatives on liver carcinogenesis may be attributed to retention of p53 and CRM1 proteins in the nucleus, an event that may trigger activation of p53-mediated apoptotic cell death in neoplastic cells. |
| Databáze: | OpenAIRE |
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