Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer

Daisuke Uchida, Hidenori Shiraha, Hironari Katou, Teruya Nagahara, Masaya Iwamuro, Junro Kataoka, Shigeru Horiguchi, Masami Watanabe, Akinobu Takaki, Kazuhiro Nouso, Yasutomo Nasu, Takahito Yagi, Hiromi Kumon, Kazuhide Yamamoto

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Abstract

Background and Aim: The reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer. Methods: REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine. Results: The REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling. Conclusions: Ad-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.

Original languageEnglish
Pages (from-to)973-983
Number of pages11
JournalJournal of Gastroenterology and Hepatology (Australia)
Volume29
Issue number5
DOIs
Publication statusPublished - 2014

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Pancreatic Neoplasms
Adenoviridae
Genetic Therapy
gemcitabine
Apoptosis
Cell Line
Therapeutics
Growth
Neoplasms
Autophagy
Therapeutic Uses
Sirolimus
Tumor Suppressor Genes
Immunoblotting
Heterografts
Genes
Prostatic Neoplasms
Down-Regulation
Immunohistochemistry

Keywords

  • Apoptosis
  • Autophagy
  • Dickkopf-related protein
  • Gene therapy
  • mTOR pathway

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology
  • Medicine(all)

Cite this

@article{89bd7323d6344012b5970a064ccb062c,
title = "Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer",
abstract = "Background and Aim: The reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer. Methods: REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine. Results: The REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling. Conclusions: Ad-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.",
keywords = "Apoptosis, Autophagy, Dickkopf-related protein, Gene therapy, mTOR pathway",
author = "Daisuke Uchida and Hidenori Shiraha and Hironari Katou and Teruya Nagahara and Masaya Iwamuro and Junro Kataoka and Shigeru Horiguchi and Masami Watanabe and Akinobu Takaki and Kazuhiro Nouso and Yasutomo Nasu and Takahito Yagi and Hiromi Kumon and Kazuhide Yamamoto",
year = "2014",
doi = "10.1111/jgh.12501",
language = "English",
volume = "29",
pages = "973--983",
journal = "Journal of Gastroenterology and Hepatology (Australia)",
issn = "0815-9319",
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number = "5",

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TY - JOUR

T1 - Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer

AU - Uchida, Daisuke

AU - Shiraha, Hidenori

AU - Katou, Hironari

AU - Nagahara, Teruya

AU - Iwamuro, Masaya

AU - Kataoka, Junro

AU - Horiguchi, Shigeru

AU - Watanabe, Masami

AU - Takaki, Akinobu

AU - Nouso, Kazuhiro

AU - Nasu, Yasutomo

AU - Yagi, Takahito

AU - Kumon, Hiromi

AU - Yamamoto, Kazuhide

PY - 2014

Y1 - 2014

N2 - Background and Aim: The reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer. Methods: REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine. Results: The REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling. Conclusions: Ad-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.

AB - Background and Aim: The reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer. Methods: REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine. Results: The REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling. Conclusions: Ad-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.

KW - Apoptosis

KW - Autophagy

KW - Dickkopf-related protein

KW - Gene therapy

KW - mTOR pathway

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U2 - 10.1111/jgh.12501

DO - 10.1111/jgh.12501

M3 - Article

C2 - 24372695

AN - SCOPUS:84898883205

VL - 29

SP - 973

EP - 983

JO - Journal of Gastroenterology and Hepatology (Australia)

JF - Journal of Gastroenterology and Hepatology (Australia)

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