Increase in the nuclear localization of PTEN by the Toxoplasma GRA16 protein and subsequent induction of p53-dependent apoptosis and anticancer effect

Sang-Gyun Kim, Seung-Hwan Seo, Ji-Hun Shin, Jung-Pyo Yang, Sang Hyung Lee, Eun-Hee Shin

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

This study investigated the efficacy of Toxoplasma GRA16, which binds to herpes virus-associated ubiquitin-specific protease (HAUSP), in anticancer treatment, and whether the expression of GRA16 in genetically modified hepatocellular carcinoma (HCC) cells (GRA16-p53-wild HepG2 and GRA16-p53-null Hep3B) regulates PTEN because alterations in phosphatase and tensin homologue (PTEN) and p53 are vital in liver carcinogenesis and the abnormal p53 gene appears in HCC. For this purpose, we established the GRA16 cell lines using the pBABE retrovirus system, assessed the detailed mechanism of PTEN regulation in vitro and established the anticancer effect in xenograft mice. Our study showed that cell proliferation, antiapoptotic factors, p-AKT/AKT ratio, cell migration and invasive activity were decreased in GRA16-stable HepG2 cells. Conversely, the apoptotic factors PTEN and p53 and apoptotic cells were elevated in GRA16-stable HepG2 cells but not in Hep3B cells. The change in MDM2 was inconspicuous in both HepG2 and Hep3B; however, the PTEN level was remarkably elevated in HepG2 but not in Hep3B. HAUSP-bound GRA16 preferentially increased p53 stabilization by the nuclear localization of PTEN rather than MDM2-dependent mechanisms. These molecular changes appeared to correlate with the decreased tumour mass in GRA16-stable-HepG2 cell-xenograft nude mice. This study establishes that GRA16 is a HAUSP inhibitor that targets the nuclear localization of PTEN and induces the anticancer effect in a p53-dependent manner. The efficacy of GRA16 could be newly highlighted in HCC treatment in a p53-dependent manner.

Original languageEnglish
Pages (from-to)3234-3245
Number of pages12
JournalJournal of Cellular and Molecular Medicine
Volume23
Issue number5
Early online date4 Mar 2019
DOIs
StatePublished - 1 May 2019

Fingerprint

Toxoplasma
Phosphoric Monoester Hydrolases
Apoptosis
Ubiquitin-Specific Proteases
Hep G2 Cells
Proteins
Hepatocellular Carcinoma
Viruses
Heterografts
p53 Genes
Retroviridae
Tensins
Protease Inhibitors
Nude Mice
Cell Movement
Carcinogenesis
Cell Proliferation
Cell Line
Liver
Neoplasms

Keywords

  • cell cycle arrest
  • GRA16-stable cell line
  • HAUSP
  • Hep3B
  • hepatocellular carcinoma
  • HepG2
  • p53
  • PTEN
  • Toxoplasma GRA16
  • USP7

Cite this

@article{b9bcf8e11daf40888af5e61e98a39551,
title = "Increase in the nuclear localization of PTEN by the Toxoplasma GRA16 protein and subsequent induction of p53-dependent apoptosis and anticancer effect",
abstract = "This study investigated the efficacy of Toxoplasma GRA16, which binds to herpes virus-associated ubiquitin-specific protease (HAUSP), in anticancer treatment, and whether the expression of GRA16 in genetically modified hepatocellular carcinoma (HCC) cells (GRA16-p53-wild HepG2 and GRA16-p53-null Hep3B) regulates PTEN because alterations in phosphatase and tensin homologue (PTEN) and p53 are vital in liver carcinogenesis and the abnormal p53 gene appears in HCC. For this purpose, we established the GRA16 cell lines using the pBABE retrovirus system, assessed the detailed mechanism of PTEN regulation in vitro and established the anticancer effect in xenograft mice. Our study showed that cell proliferation, antiapoptotic factors, p-AKT/AKT ratio, cell migration and invasive activity were decreased in GRA16-stable HepG2 cells. Conversely, the apoptotic factors PTEN and p53 and apoptotic cells were elevated in GRA16-stable HepG2 cells but not in Hep3B cells. The change in MDM2 was inconspicuous in both HepG2 and Hep3B; however, the PTEN level was remarkably elevated in HepG2 but not in Hep3B. HAUSP-bound GRA16 preferentially increased p53 stabilization by the nuclear localization of PTEN rather than MDM2-dependent mechanisms. These molecular changes appeared to correlate with the decreased tumour mass in GRA16-stable-HepG2 cell-xenograft nude mice. This study establishes that GRA16 is a HAUSP inhibitor that targets the nuclear localization of PTEN and induces the anticancer effect in a p53-dependent manner. The efficacy of GRA16 could be newly highlighted in HCC treatment in a p53-dependent manner.",
keywords = "cell cycle arrest, GRA16-stable cell line, HAUSP, Hep3B, hepatocellular carcinoma, HepG2, p53, PTEN, Toxoplasma GRA16, USP7",
author = "Sang-Gyun Kim and Seung-Hwan Seo and Ji-Hun Shin and Jung-Pyo Yang and Lee, {Sang Hyung} and Eun-Hee Shin",
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Increase in the nuclear localization of PTEN by the Toxoplasma GRA16 protein and subsequent induction of p53-dependent apoptosis and anticancer effect. / Kim, Sang-Gyun; Seo, Seung-Hwan; Shin, Ji-Hun; Yang, Jung-Pyo; Lee, Sang Hyung; Shin, Eun-Hee.

In: Journal of Cellular and Molecular Medicine, Vol. 23, No. 5, 01.05.2019, p. 3234-3245.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Increase in the nuclear localization of PTEN by the Toxoplasma GRA16 protein and subsequent induction of p53-dependent apoptosis and anticancer effect

AU - Kim, Sang-Gyun

AU - Seo, Seung-Hwan

AU - Shin, Ji-Hun

AU - Yang, Jung-Pyo

AU - Lee, Sang Hyung

AU - Shin, Eun-Hee

N1 - © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - This study investigated the efficacy of Toxoplasma GRA16, which binds to herpes virus-associated ubiquitin-specific protease (HAUSP), in anticancer treatment, and whether the expression of GRA16 in genetically modified hepatocellular carcinoma (HCC) cells (GRA16-p53-wild HepG2 and GRA16-p53-null Hep3B) regulates PTEN because alterations in phosphatase and tensin homologue (PTEN) and p53 are vital in liver carcinogenesis and the abnormal p53 gene appears in HCC. For this purpose, we established the GRA16 cell lines using the pBABE retrovirus system, assessed the detailed mechanism of PTEN regulation in vitro and established the anticancer effect in xenograft mice. Our study showed that cell proliferation, antiapoptotic factors, p-AKT/AKT ratio, cell migration and invasive activity were decreased in GRA16-stable HepG2 cells. Conversely, the apoptotic factors PTEN and p53 and apoptotic cells were elevated in GRA16-stable HepG2 cells but not in Hep3B cells. The change in MDM2 was inconspicuous in both HepG2 and Hep3B; however, the PTEN level was remarkably elevated in HepG2 but not in Hep3B. HAUSP-bound GRA16 preferentially increased p53 stabilization by the nuclear localization of PTEN rather than MDM2-dependent mechanisms. These molecular changes appeared to correlate with the decreased tumour mass in GRA16-stable-HepG2 cell-xenograft nude mice. This study establishes that GRA16 is a HAUSP inhibitor that targets the nuclear localization of PTEN and induces the anticancer effect in a p53-dependent manner. The efficacy of GRA16 could be newly highlighted in HCC treatment in a p53-dependent manner.

AB - This study investigated the efficacy of Toxoplasma GRA16, which binds to herpes virus-associated ubiquitin-specific protease (HAUSP), in anticancer treatment, and whether the expression of GRA16 in genetically modified hepatocellular carcinoma (HCC) cells (GRA16-p53-wild HepG2 and GRA16-p53-null Hep3B) regulates PTEN because alterations in phosphatase and tensin homologue (PTEN) and p53 are vital in liver carcinogenesis and the abnormal p53 gene appears in HCC. For this purpose, we established the GRA16 cell lines using the pBABE retrovirus system, assessed the detailed mechanism of PTEN regulation in vitro and established the anticancer effect in xenograft mice. Our study showed that cell proliferation, antiapoptotic factors, p-AKT/AKT ratio, cell migration and invasive activity were decreased in GRA16-stable HepG2 cells. Conversely, the apoptotic factors PTEN and p53 and apoptotic cells were elevated in GRA16-stable HepG2 cells but not in Hep3B cells. The change in MDM2 was inconspicuous in both HepG2 and Hep3B; however, the PTEN level was remarkably elevated in HepG2 but not in Hep3B. HAUSP-bound GRA16 preferentially increased p53 stabilization by the nuclear localization of PTEN rather than MDM2-dependent mechanisms. These molecular changes appeared to correlate with the decreased tumour mass in GRA16-stable-HepG2 cell-xenograft nude mice. This study establishes that GRA16 is a HAUSP inhibitor that targets the nuclear localization of PTEN and induces the anticancer effect in a p53-dependent manner. The efficacy of GRA16 could be newly highlighted in HCC treatment in a p53-dependent manner.

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KW - GRA16-stable cell line

KW - HAUSP

KW - Hep3B

KW - hepatocellular carcinoma

KW - HepG2

KW - p53

KW - PTEN

KW - Toxoplasma GRA16

KW - USP7

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U2 - 10.1111/jcmm.14207

DO - 10.1111/jcmm.14207

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VL - 23

SP - 3234

EP - 3245

JO - Journal of Cellular and Molecular Medicine

JF - Journal of Cellular and Molecular Medicine

SN - 1582-1838

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