Effects of small interfering RNA targeting thymidylate synthase on survival of ACC3 cells from salivary adenoid cystic carcinoma.
Effects of small interfering RNA targeting thymidylate synthase on survival of ACC3 cells from salivary adenoid cystic carcinoma.
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DOI：
10.1186/1471-2407-8-348
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发表时间：
2008-11-26
期刊：
影响因子：
3.8
通讯作者：
Shinkawa, Hideichi
中科院分区：
文献类型：
--
作者：
Shirasaki, Takashi;Maruya, Shin-ichiro;Mizukami, Hiroki;Kakehata, Seiji;Kurotaki, Hidekachi;Yagihashi, Soroku;Shinkawa, Hideichi
胸苷酸合成酶（Thymidylate synthase， TS）是癌症化疗的重要靶点，在结直肠癌、头颈癌等多种癌症中，TS的高表达与预后不良或难治性疾病相关。虽然已知TS调节细胞周期和转录因子，但其作为腺样囊性癌（ACC）治疗靶点的效力尚未得到充分探索。用靶向TS基因的siRNA转染ACC细胞系（ACC3），体外观察其对细胞生长的抑制作用和诱导凋亡相关分子的作用。此外，使用异种移植模型评估TS siRNA对肿瘤进展的体内影响。我们的研究结果表明，ACC3细胞的TS表达明显高于非癌细胞系，诱导TS siRNA可抑制细胞增殖。这种效应与p53、p21、活性caspase-3和s期积累的增加有关。我们还发现亚精胺/精胺n1 -乙酰转移酶（SSAT）上调，这是一种多胺代谢酶。此外，在异种移植瘤模型中，胶原间质传递的TS siRNA通过诱导细胞凋亡显示出显著的细胞抑制作用。TS可能是一个重要的治疗靶点，靶向TS的siRNA可能在ACC中具有潜在的治疗价值。
Thymidylate synthase (TS) is an important target for chemotherapeutic treatment of cancer and high expression of TS has been associated with poor prognosis or refractory disease in several cancers including colorectal and head and neck cancer. Although TS is known to regulate cell cycles and transcription factors, its potency as a therapeutic target has not been fully explored in adenoid cystic carcinoma (ACC). An ACC cell line (ACC3) was transfected with siRNA targeting the TS gene and inhibition of cell growth and induction of apoptosis-associated molecules were evaluated in vitro. In addition, the in vivo effect of TS siRNA on tumor progression was assessed using a xenograft model. Our results demonstrated that ACC3 cells showed significantly higher TS expression than non-cancer cell lines and the induction of TS siRNA led to inhibition of cell proliferation. The effect was associated with an increase in p53, p21, and active caspase-3 and S-phase accumulation. We also found up-regulation of spermidine/spermine N1-acetyltransferase (SSAT), a polyamine metabolic enzyme. Furthermore, treatment with TS siRNA delivered by atelocollagen showed a significant cytostatic effect through the induction of apoptosis in a xenograft model. TS may be an important therapeutic target and siRNA targeting TS may be of potential therapeutic value in ACC.
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