Department of Urology, Ibaraki Clinical Education and Training Center, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Int J Oncol. 2013 Feb;42(2):543-8. doi: 10.3892/ijo.2012.1752. Epub 2012 Dec 24.
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.
p16（INK4a）（p16）是膀胱癌发展过程中的关键分子，它可以抑制周期蛋白依赖性激酶（CDKs）的活性，并使视网膜母细胞瘤蛋白（pRb）保持在其活性低磷酸化状态。研究发现，p16 抗肿瘤肽通过 Wr-T 肽转运系统恢复 p16 功能，可显著抑制侵袭性白血病/淋巴瘤的生长，在此基础上，本研究采用小鼠 p16 肽（m-p16）对 p16 缺失型小鼠膀胱癌进行了系统治疗。体外分析表明，p16 转导可浓度依赖性地抑制 p16 缺失型膀胱癌细胞的生长及其 pRb 的过度磷酸化。在动物模型中，将 p16 缺失型 MBT-2 细胞皮下注射到 KSN/SKC 裸鼠中。与对照组磷酸盐缓冲盐水（PBS）注射相比，心脏注射 Wr-T 系统递送 m-p16 肽可显著抑制实体 MBT-2 肿瘤的生长。TUNEL 染色的组织学检查显示，细胞凋亡增加，pRb 磷酸化受到抑制。因此，p16 的系统肽递释可恢复 pRb 的低磷酸化，可能是膀胱癌治疗的一种有用工具。
