Research Papers:

Suppressing activity of tributyrin on hepatocarcinogenesis is associated with inhibiting the p53-CRM1 interaction and changing the cellular compartmentalization of p53 protein

Juliana F. Ortega, Aline de Conti, Volodymyr Tryndyak, Kelly S. Furtado, Renato Heidor, Maria Aderuza Horst, Laura Helena Gasparini Fernandes, Paulo Eduardo Latorre Martins Tavares, Marta Pogribna, Svitlana Shpyleva, Frederick A. Beland, Igor P. Pogribny and Fernando Salvador Moreno _

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Oncotarget. 2016; 7:24339-24347. https://doi.org/10.18632/oncotarget.8248

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Juliana F. Ortega1, Aline de Conti2, Volodymyr Tryndyak2, Kelly S. Furtado1, Renato Heidor1, Maria Aderuza Horst1, Laura Helena Gasparini Fernandes1, Paulo Eduardo Latorre Martins Tavares1, Marta Pogribna2, Svitlana Shpyleva2, Frederick A. Beland2, Igor P. Pogribny2, Fernando Salvador Moreno1

1Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil

2Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA

Correspondence to:

Fernando Salvador Moreno, e-mail: rmoreno@usp.br

Igor P. Pogribny, e-mail: igor.pogribny@fda.hhs.gov

Keywords: hepatocarcinogenesis, chemoprevention, tributyrin, p53 subcellular localization, CRM1

Received: January 30, 2016     Accepted: February 28, 2016     Published: March 22, 2016


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.

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