Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Int J Cancer. 2010 Jul 1;127(1):195-206. doi: 10.1002/ijc.25025.
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-kappaB 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-kappaB were overexpressed. The positive expression of FAK correlated notably with lymph node metastasis and cellular differentiation. Positive expressions of Akt and NF-kappaB were significantly related to cellular differentiation and lymph node metastasis, respectively. Furthermore, positive expression of FAK correlated with that of Akt and NF-kappaB. 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-kappaB. These results indicate that suppressing FAK expression potentiated 5-FU-induced cytotoxicity and contributed to its chemosensitizing effect by suppressing Akt/NF-kappaB 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-kappaB.
多细胞耐药性（MCR）是由于在三维培养时形成广泛的细胞-细胞连接而产生的多细胞球体（MCS），这限制了实体瘤的临床治疗效果。粘着斑激酶（FAK）在细胞凋亡、存活和细胞与其细胞外基质之间的细胞黏附中起着重要作用。在本研究中，我们研究了粘着斑激酶（FAK）、Akt 和 NF-κB 在人结直肠癌（CRC）中的表达，以及 FAK 基因沉默对结肠癌 MCS 培养细胞中 MCS 形成和 5-氟尿嘧啶（5-FU）化学敏感性的影响。在 CRC 样本中，FAK、Akt 和 NF-κB 过度表达。FAK 的阳性表达与淋巴结转移和细胞分化显著相关。Akt 和 NF-κB 的阳性表达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-κB 的阳性表达相关。针对 FAK 的短发夹 RNA 显著抑制 FAK 的表达。FAK 敲低逆转了 MCS 的形成和聚集，显著降低了 5-FU 的 50%抑制浓度，并显著增加了 MCS 培养细胞的凋亡。这些作用与 Akt 和 NF-κB 水平的降低有关。这些结果表明，抑制 FAK 表达通过抑制 Akt/NF-κB 信号通路增强了 5-FU 诱导的细胞毒性，并对结肠癌 MCS 培养细胞的化学增敏作用有贡献。这些数据还表明，FAK 通过 FAK/Akt/NF-κB 存活信号通路介导 CRC 的 MCR。
