Sato, Shoki Hokkaido University
Nakamura, Toru Hokkaido University
Tsuchikawa, Takahiro Hokkaido University
Kushibiki, Toshihiro Hokkaido University
Hontani, Kouji Hokkaido University
Takahashi, Mizuna Hokkaido University
Inoko, Kazuho Hokkaido University
Takano, Hironobu Hokkaido University
Abe, Hirotake Hokkaido University
Takeuchi, Shintaro Hokkaido University
Ono, Masato Hokkaido University
Kuwabara, Shota Hokkaido University
Umemoto, Kazufumi Hokkaido University
Suzuki, Tomohiro Hokkaido University
Sato, Osamu Hokkaido University
Nakamura, Yusuke The University of Chicago
Hirano, Satoshi Hokkaido University
pancreatic ductal adenocarcinoma
molecular target therapy
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.
Impact Journals, LLC
Copyright: Sato et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0)(https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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