Systemic transduction of p16INK4A antitumor peptide inhibits the growth of MBT-2 mouse bladder tumor cell line grafts
Systemic transduction of p16INK4A antitumor peptide inhibits the growth of MBT-2 mouse bladder tumor cell line grafts
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DOI：
10.3892/ijo.2012.1752
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发表时间：
2013-02-01
影响因子：
5.2
通讯作者：
Nishiyama, Hiroyuki
中科院分区：
文献类型：
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作者：
Shimazui, Toru;Yoshikawa, Kazuhiro;Nishiyama, Hiroyuki
p16(INK4a) (p16) 是膀胱肿瘤发生的关键分子，可抑制细胞周期蛋白依赖性激酶 (CDK) 的活性，并维持视网膜母细胞瘤蛋白 (pRb) 的活性低磷酸化状态。在发现 p16 抗肿瘤肽通过使用 Wr-T 肽转运蛋白系统恢复 p16 功能来显着抑制侵袭性白血病/淋巴瘤的生长后，在本研究中，我们开发了一种使用小鼠 p16 肽（m-p16）治疗皮下 p16 缺失小鼠膀胱肿瘤的全身疗法。体外分析表明，p16 转导以浓度依赖性方式抑制 p16 缺失的膀胱肿瘤细胞的生长及其 pRb 的过度磷酸化。在动物模型中，将 p16-null MBT-2 细胞皮下注射到 KSN/SKC 裸鼠体内。与对照磷酸盐缓冲盐水 (PBS) 注射相比，通过心脏注射使用 Wr-T 全身递送 m-p16 肽可显着抑制实体 MBT-2 肿瘤的生长。 TUNEL染色的组织学检查显示细胞凋亡增加并且pRb磷酸化受到抑制。因此，p16 的全身肽递送恢复了 pRb 的低磷酸化，并且可能是治疗膀胱肿瘤的有用工具。
p16(INK4a) (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 leukemia/lymphoma 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.