title: Suppressing activity of tributyrin on hepatocarcinogenesis is associated with inhibiting the p53-CRM1 interaction and changing the cellular compartmentalization of p53 protein.
abstract: 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.
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Juliana F
authors.initials: JF
authors.lastname: Ortega
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA.
authors.forename: Aline
authors.initials: A
authors.lastname: de Conti
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Tryndyak
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Furtado
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Renato
authors.initials: R
authors.lastname: Heidor
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Maria Aderuza
authors.initials: MA
authors.lastname: Horst
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Laura Helena Gasparini
authors.initials: LH
authors.lastname: Fernandes
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Paulo Eduardo Latorre Martins
authors.initials: PE
authors.lastname: Tavares
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Pogribna
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Shpyleva
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
authors.affiliation: Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Fernando Salvador
authors.initials: FS
authors.lastname: Moreno
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D020148:Butyric Acid / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002451:Cell Compartmentation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000097606:Exportin 1 Protein
chemical_list: D020148:Butyric Acid; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein; C005830:tributyrin
keywords: CRM1; chemoprevention; hepatocarcinogenesis; p53 subcellular localization; tributyrin