Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer.
Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer.
复制标题
头颈癌中 MMP 敏感的随意转导。
DOI：
10.1016/j.omto.2019.02.003
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Sunavala-Dossabhoy,Gulshan
中科院分区：
文献类型：
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作者：
Nair,RenjithParameswaran;TimiriShanmugam,PrakashSrinivasan;Sunavala-Dossabhoy,Gulshan
口服放射毒性通常是癌症治疗的一个限制因素。在此之前，我们证明了在唾液腺中转移细胞可穿透的、TAT融合的TLK1B(TLK1B)蛋白有效地缓解了辐射引起的唾液功能障碍。然而，与大多数放射防护剂一样，TLK1B可能存在限制癌症治疗效果的风险。因此，这项研究的中心目标是将TLK1B重新设计为正常细胞的选择性辐射防护剂。基质金属蛋白酶(MMPs)等酶降解细胞外基质是侵袭性肿瘤的标志。膜型1-基质金属蛋白酶(MT1-MMP；又称MMP14)在包括头颈部鳞状细胞癌(HNSCC)在内的多种癌症中的表达增加。为了将TLK1B的转导限制在正常细胞中，我们使该蛋白容易被MT1-MMP裂解，前提是HNSCC细胞表面MT1-MMP高表达会抑制TLK1B的内化。两个最佳的MT1-MMPs敏感序列(MS)被确定，当与TAT-TLK1B结合时，排除了其进入HNSCC、SCC40的细胞，但不包括永生化唾液腺泡细胞NS-SV-AC。重要的是，在裸鼠移植瘤模型中，给予携带MS的TAT-TLK1B并不影响肿瘤对辐射的敏感性。我们的结论是，对基质金属蛋白酶敏感的TLK1B可能是一种有吸引力的治疗方法，可以在不影响癌症治疗效果的情况下减轻唾液的放射毒性。
Oral radiotoxicity is often a limiting factor in cancer treatment. Previously, we demonstrated that transfer of cell-permeable, TAT-fusion Tousled-like kinase 1B (TLK1B) protein in salivary glands effectively mitigates radiation-induced salivary dysfunction. However, similar to most radioprotectors, TLK1B can carry the risk of limiting cancer treatment efficacy. The central goal of the study was, therefore, to reengineer TLK1B as a selective radioprotector of normal cells. Degradation of the extracellular matrix by proteases such as matrix metalloproteinases (MMPs) is a hallmark of aggressive tumors. Increased expression of membrane type 1-MMP (MT1-MMP; also called MMP14) is observed in a variety of cancers including head and neck squamous cell carcinoma (HNSCC). To limit TLK1B transduction to normal cells, we rendered the protein susceptible to MT1-MMP cleavage on the premise that high expression of MT1-MMP on the cell surface of HNSCC will suppress TLK1B internalization. Two optimal MT1-MMP-sensitive sequences (MS) were identified that when incorporated in TAT-TLK1B excluded its cellular entry in HNSCC, SCC40, but not immortalized salivary acinar cells, NS-SV-AC. Importantly, administration of MS-harboring TAT-TLK1B did not affect the sensitivity of tumors to radiation in a nude mouse xenograft tumor model. We conclude that a MMP-sensitive TLK1B can be an attractive therapeutic to allay salivary radiotoxicity without compromising cancer treatment efficacy.