The effect of focal adhesion kinase gene silencing on 5-fluorouracil chemosensitivity involves an Akt/NF-κB signaling pathway in colorectal carcinomas
The effect of focal adhesion kinase gene silencing on 5-fluorouracil chemosensitivity involves an Akt/NF-κB signaling pathway in colorectal carcinomas
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DOI：
10.1002/ijc.25025
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发表时间：
2010-07-01
影响因子：
6.4
通讯作者：
Liang, Houjie
中科院分区：
文献类型：
--
作者：
Chen, Yuying;Wang, Zhanxiang;Liang, Houjie
多细胞耐药(MCR)是由于多细胞球体(MCSs)在三维培养时与广泛的细胞连接形成的，限制了实体瘤的临床治疗效果。粘着斑激酶(FAK)在细胞与细胞外基质之间的凋亡、存活和细胞黏附过程中发挥着重要作用。本研究探讨FAK、Akt和核因子-kappaB在结直肠癌组织中的表达，以及FAK基因沉默对结肠癌MCSs形成和5-FU化疗敏感性的影响。在大肠癌组织中，FAK、Akt和NF-kappa B过表达。FAK阳性表达与淋巴结转移和细胞分化程度显著相关。Akt和NF-kappa B的阳性表达分别与细胞分化和淋巴结转移显著相关。此外，FAK的阳性表达与Akt和NF-kappa B的表达呈正相关。针对FAK的小发夹RNA显著抑制了FAK的表达。FAK基因敲除可逆转MCSs的形成和聚集，显著降低5-FU的半数抑制浓度，显著增加MCS培养细胞的凋亡率。这些结果表明，抑制FAK的表达增强了5-FU诱导的细胞毒作用，并通过抑制Akt/NF-kappa B信号通路参与了5-FU的化疗增敏作用。这些数据还表明，FAK通过生存信号通路FAK/Akt/NF-kappa B介导了结直肠癌的MCR。
Multicellular resistance (MCR) is produced because multicellular spheroids (MCSs) are formed with a broad cell cell connection when cultured in three-dimensions, which limits the clinical treatment efficacy in solid tumors. Focal adhesion kinase (FAK) plays an important role in apoptosis, survival and cell adhesion between cells and their extracellular matrix. In this study, we investigated the expressions of FAK, Akt and NF-kappa B in human colorectal cancer (CRC), and the effects of FAK gene silencing on MCSs formation and 5-fluorouracil (5-FU) chemosensitivity in colon carcinoma MCSs culture cells. In CRC samples, FAK, Akt and NF-kappa B were overexpressed. The positive expression of FAK correlated notably with lymph node metastasis and cellular differentiation. Positive expressions of Akt and NF-kappa B were significantly related to cellular differentiation and lymph node metastasis, respectively. Furthermore, positive expression of FAK correlated with that of Akt and NF-kappa B. The expression of FAK was inhibited significantly by a small hairpin RNA targeting FAK. Knockdown of FAK reversed the formation and aggregation of MCSs, significantly decreased the 50% inhibitory concentration of 5-FU, and markedly increased MCS culture cells apoptosis. These effects were associated with reduced levels of Akt and NF-kappa B. These results indicate that suppressing FAK expression potentiated 5-FU-induced cytotoxicity and contributed to its chemosensitizing effect by suppressing Akt/NF-kappa B signaling in colon carcinoma MCS culture cells. These data also imply that FAK mediates MCR of CRC through the survival signaling pathway FAK/Akt/NF-kappa B.