Oncotarget

Research Papers:

Molecular targeting of cell-permeable peptide inhibits pancreatic ductal adenocarcinoma cell proliferation

Shoki Sato, Toru Nakamura _, Toyomasa Katagiri, Takahiro Tsuchikawa, Toshihiro Kushibiki, Kouji Hontani, Mizuna Takahashi, Kazuho Inoko, Hironobu Takano, Hirotake Abe, Shintaro Takeuchi, Masato Ono, Shota Kuwabara, Kazufumi Umemoto, Tomohiro Suzuki, Osamu Sato, Yusuke Nakamura and Satoshi Hirano

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Oncotarget. 2017; 8:113662-113672. https://doi.org/10.18632/oncotarget.21939

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Abstract

Shoki Sato1, Toru Nakamura1, Toyomasa Katagiri2, Takahiro Tsuchikawa1, Toshihiro Kushibiki1, Kouji Hontani1, Mizuna Takahashi1, Kazuho Inoko1, Hironobu Takano1, Hirotake Abe1, Shintaro Takeuchi1, Masato Ono1, Shota Kuwabara1, Kazufumi Umemoto1, Tomohiro Suzuki1, Osamu Sato1, Yusuke Nakamura3 and Satoshi Hirano1

1Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan

2Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan

3Department of Medicine and Surgery, The University of Chicago, Chicago, IL, USA

Correspondence to:

Toru Nakamura, email: torunakamura@med.hokudai.ac.jp

Keywords: C16orf74; pancreatic ductal adenocarcinoma; cell-permeable peptide; molecular target therapy

Received: May 04, 2017    Accepted: July 26, 2017    Published: October 19, 2017

ABSTRACT

Background: Chromosome 16 open reading frame 74 (C16orf74) is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and is involved in cancer cell proliferation and invasion through binding to calcineurin (CN). Therefore, C16orf74 is a good target for the development of a PDAC treatment. A cell-permeable dominant-negative (DN) peptide that can inhibit the C16orf74/CN interaction was designed to examine whether this peptide can inhibit PDAC cell proliferation in vitro and in vivo.

Method: TheDN-C16orf74 peptide, which corresponds to the portion of C16orf74 that interacts with CN, was synthesized, and we assessed its anti-tumor activity in proliferation assays with human PDAC cells and the underlying molecular signaling pathway. Using an orthotopic xenograft model of PDAC, we treated mice intraperitoneally with phosphate-buffered saline (PBS), control peptide, or DN-C16orf74 and analyzed the tumor-suppressive effects.

Result: DN-C16orf74 inhibited the binding of C16orf74 to CN in an immunoprecipitation assay. DN-C16orf74 suppressed PDAC cell proliferation, and the level of suppression depended on the expression levels of C16orf74 in vitro. DN-C16orf74 also exhibited anti-tumor effects in orthotopic xenograft model. Furthermore, the tumor-suppressive effect was associated with inhibition of the phosphorylation of Akt and mTOR.

Conclusion: The cell-permeable peptide DN-C16orf74 has a strong anti-tumor effect against PDAC in vitro and in vivo.


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