2. Academic Validation
  3. Subcellular distribution and Nrf2/Keap1-interacting properties of Glutathione S-transferase P in hepatocellular carcinoma

Subcellular distribution and Nrf2/Keap1-interacting properties of Glutathione S-transferase P in hepatocellular carcinoma

  • Arch Biochem Biophys. 2024 Jul:757:110043. doi: 10.1016/j.abb.2024.110043.
Desirée Bartolini 1,  Anna Maria Stabile 2,  Anna Migni 3,  Fabio Gurrado 4,  Gessica Lioci 5,  Francesca De Franco 6,  Martina Mandarano 7,  Gianluca Svegliati-Baroni 8,  Manlio Di Cristina 9,  Guido Bellezza 10,  Mario Rende 11,  Francesco Galli 12
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Perugia, 06126, Perugia, Italy. Electronic address: desiree.bartolini@unipg.it.
  • 2 Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy. Electronic address: anna.stabile@unipg.it.
  • 3 Department of Pharmaceutical Sciences, University of Perugia, 06126, Perugia, Italy. Electronic address: annamigni4@gmail.com.
  • 4 Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy. Electronic address: gurrado.fabio@gmail.com.
  • 5 Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy. Electronic address: gessicalioci@gmail.com.
  • 6 Tes Pharma s.r.l., Corciano, 06073, Perugia, Italy. Electronic address: fdefranco@tespharma.com.
  • 7 Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy.
  • 8 Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy; Obesity Center, Marche Polytechnic University, Ancona, Italy and Liver Injury and Transplant Unit, Ancona, Italy. Electronic address: gsvegliati@gmail.com.
  • 9 Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy. Electronic address: manlio.dicristina@unipg.it.
  • 10 Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy. Electronic address: guido.bellezza@unipg.it.
  • 11 Department of Medicine and Surgery, University of Perugia, 06132, Perugia, Italy. Electronic address: mario.rende@unipg.it.
  • 12 Department of Pharmaceutical Sciences, University of Perugia, 06126, Perugia, Italy. Electronic address: francesco.galli@unipg.it.
PMID: 38789086 DOI: 10.1016/j.abb.2024.110043
Abstract

The oncogene and drug metabolism enzyme Glutathione S-transferase P (GSTP) is also a GSH-dependent chaperone of signal transduction and transcriptional proteins with key role in liver carcinogenesis. In this study, we explored this role of GSTP in hepatocellular carcinoma (HCC) investigating the possible interaction of this protein with one of its transcription factor and metronome of the Cancer cell redox, namely the nuclear factor erythroid 2-related factor 2 (Nrf2). Expression, cellular distribution, and function as glutathionylation factor of GSTP1-1 isoform were investigated in the mouse model of N-nitrosodiethylamine (DEN)-induced HCC and in vitro in human HCC cell lines. The physical and functional interaction of GSTP protein with Nrf2 and Keap1 were investigated by immunoprecipitation and gene manipulation experiments. GSTP protein increased its liver expression, enzymatic activity and nuclear levels during DEN-induced tumor development in mice; protein glutathionylation (PSSG) was increased in the tumor masses. Higher levels and a preferential nuclear localization of GSTP protein were also observed in HepG2 and Huh-7 hepatocarcinoma cells compared to HepaRG non-cancerous cells, along with increased basal and Ebselen-stimulated levels of free GSH and PSSG. GSTP activity inhibition with the GSH analogue EZT induced apoptotic cell death in HCC cells. Hepatic Nrf2 and c-Jun, two transcription factors involved in GSTP expression and GSH biosynthesis, were induced in DEN-HCC compared to control animals; the Nrf2 inhibitory proteins Keap1 and β-TrCP also increased and oligomeric forms of GSTP co-immunoprecipitated with both Nrf2 and Keap1. Nrf2 nuclear translocation and β-TrCP expression also increased in HCC cells, and GSTP transfection in HepaRG cells induced Nrf2 activation. In conclusion, GSTP expression and subcellular distribution are modified in HCC cells and apparently contribute to the GSH-dependent reprogramming of the cellular redox in this type of Cancer directly influencing the transcriptional system Nrf2/Keap1.

Keywords

DEN; GSTP; Glutathione; HCC; Hepatocellular carcinoma; Liver cancer; N-nitrosodiethylamine; Nrf2.

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