Systemic transduction of p16INK4A antitumor peptide inhibits the growth of MBT-2 mouse bladder tumor cell line grafts

Shimazui,Toru; Yoshikawa,Kazuhiro; Miyazaki,Jun; Kojima,Takahiro; Inai,Hiromu; Ando,Satoshi; Uemura,Hirotsugu; Uchida,Kazuhiko; Nishiyama,Hiroyuki

doi:10.3892/ijo.2012.1752

Systemic transduction of p16INK4A antitumor peptide inhibits the growth of MBT-2 mouse bladder tumor cell line grafts

Authors:
- Toru Shimazui
- Kazuhiro Yoshikawa
- Jun Miyazaki
- Takahiro Kojima
- Hiromu Inai
- Satoshi Ando
- Hirotsugu Uemura
- Kazuhiko Uchida
- Hiroyuki Nishiyama
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Affiliations: Department of Urology, Ibaraki Clinical Education and Training Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, Division of Clinical Research Promotion, Aichi Medical University, Nagakute, Japan, Department of Urology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, Department of Urology, International University of Health and Welfare, Otawara, Japan, Department of Urology, Kinki University, Higashiosaka, Japan, Department of Molecular Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
Published online on: December 24, 2012 https://doi.org/10.3892/ijo.2012.1752
Pages: 543-548

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Abstract

p16INK4a (p16), a key molecule in bladder tumor development, inhibits the activities of cyclin-dependent kinases (CDKs) and maintains the retinoblastoma protein (pRb) in its active hypophosphorylated state. Following the finding that the p16 antitumor peptide dramatically inhibits the growth of aggressive leukemia̸lymphoma through the restoration of p16 function using the Wr-T peptide transporter system, in this study, we developed a systemic therapy using mouse‑p16 peptide (m‑p16) in subcutaneous p16‑null mouse bladder tumors. In vitro analysis showed that the growth of p16‑null bladder tumor cells and the hyperphosphorylation of their pRbs were inhibited by p16 transduction in a concentration‑dependent manner. In an animal model, p16‑null MBT‑2 cells were injected subcutaneously into KSN/SKC nude mice. The systemic delivery of the m‑p16 peptide using Wr‑T by cardiac injection significantly inhibited the growth of solid MBT‑2 tumors compared with the control phosphate‑buffered saline (PBS) injection. Histological examination by TUNEL staining revealed that apoptosis was increased and pRb phosphorylation was inhibited. Thus, the systemic peptide delivery of p16 restores the hypophosphorylation of pRb and may be a useful tool for the treatment of bladder tumors.

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