Preclinical development of a bifunctional cancer cell homing, PKCepsilon inhibitory peptide for the treatment of head and neck cancer.
Preclinical development of a bifunctional cancer cell homing, PKCepsilon inhibitory peptide for the treatment of head and neck cancer.
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DOI：
10.1158/0008-5472.can-08-3465
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Pan Q
中科院分区：
文献类型：
--
作者：
Bao L;Gorin MA;Zhang M;Ventura AC;Pomerantz WC;Merajver SD;Teknos TN;Mapp AK;Pan Q
头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，在一些发展中国家占所有恶性肿瘤的近50%。我们最近的工作确定了蛋白激酶Cε（PKCε）在HNSCC中建立侵袭性表型的关键和致病因素。在这项研究中，我们研究了HN 1-PKCε，一种新的双功能癌细胞归巢，PKCε抑制肽，作为HNSCC治疗的特异性和有效性。HN 1-PKCε肽是通过融合两种不同的技术设计的，并被合成为具有两个功能模块的加帽肽，HN 1（癌细胞归巢）和PKCε（特异性PKCε抑制剂），通过新型接头模块连接。与口腔上皮细胞相比，HN 1-PKCε优先内化到UMSCC 1和UMSCC 36细胞（两种HNSCC细胞系）中; UMSCC 1和UMSCC 36的阳性率分别为82.1%和86.5%，而口腔上皮细胞的阳性率为1.2%。此外，HN 1-PKCε以剂量和时间依赖性方式穿透HNSCC细胞。与这些体外观察结果一致，全身注射HN 1-PKCε导致HN 1-PKCε选择性递送至裸鼠的UMSCC 1异种移植物中。HN 1-PKCε阻断了UMSCC 1细胞中活性PKCε的转位，证实了HN 1-PKCε是一种PKCε抑制剂。HN 1-PKCε对UMSCC 1细胞的侵袭能力和细胞运动能力的抑制率分别为72 ± 2%（p <0.001，n=12）和56 ± 2%（p<0.001，n=5）。此外，体内生物发光成像显示，HN 1-PKCε显著（83 ± 1%抑制，p<0.02）延缓UMSCC 1裸鼠移植瘤的生长。我们的工作表明，双功能HN 1-PKCε抑制肽代表了一个有前途的新的治疗HNSCC的策略。
Head and neck squamous cell carcinoma (HNSCC) is the sixth most frequent cancer worldwide, comprising almost 50% of all malignancies in some developing nations. Our recent work identified protein kinase Cε (PKCε) as a critical and causative player in establishing an aggressive phenotype in HNSCC. In this study, we investigated the specificity and efficacy of HN1-PKCε, a novel bi-functional cancer cell homing, PKCε inhibitory peptide, as a treatment for HNSCC. HN1-PKCε peptide was designed by merging two separate technologies and synthesized as a capped peptide with two functional modules, HN1 (cancer cell homing) and PKCε (specific PKCε inhibitory), connected by a novel linker module. HN1-PKCε preferentially internalized into UMSCC1 and UMSCC36 cells, two HNSCC cell lines, in comparison to oral epithelial cells; 82.1% positive for UMSCC1 and 86.5% positive for UMSCC36 compared to 1.2% positive for oral epithelial cells. In addition, HN1-PKCε penetrated HNSCC cells in a dose-and time-dependent manner. Consistent with these in vitro observations, systemic injection of HN1-PKCε resulted in selective delivery of HN1-PKCε into UMSCC1 xenografts in nude mice. HN1-PKCε blocked the translocation of active PKCε in UMSCC1 cells confirming HN1-PKCε as a PKCε inhibitor. HN1-PKCε inhibited cell invasion by 72 ± 2% (p<0.001, n=12) and cell motility by 56 ± 2% (p<0.001, n=5) in UMSCC1 cells. Moreover, in vivo bioluminescence imaging demonstrated that HN1-PKCε significantly (83 ± 1% inhibition, p<0.02) retards the growth of UMSCC1 xenografts in nude mice. Our work indicates that the bi-functional HN1-PKCε inhibitory peptide represents a promising novel therapeutic strategy for HNSCC.