AKT plays a pivotal role in the acquisition of resistance to 5-fluorouracil in human squamous carcinoma cells.
AKT plays a pivotal role in the acquisition of resistance to 5-fluorouracil in human squamous carcinoma cells.
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DOI：
10.3892/mmr_00000145
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发表时间：
2009-07
影响因子：
3.4
通讯作者：
Fukka You;Kenta Aoki;Yatsuji Ito;S. Nakashima
中科院分区：
文献类型：
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作者：
Fukka You;Kenta Aoki;Yatsuji Ito;S. Nakashima
5-氟尿嘧啶（5-FU）是一种广泛使用的化疗药物，可抑制上皮性肿瘤（包括头颈部鳞状细胞癌）的生长并启动其凋亡。然而，在临床环境中经常观察到对这种药物的耐药性。认为5-FU的主要作用模式是抑制胸苷酸合成酶。参与胸苷合成的酶的过表达在某些情况下已被证明与抗性有关。然而，鳞状细胞癌耐药的详细机制尚未完全了解。在本研究中，我们研究了生存信号通路参与鳞状细胞癌细胞对5-FU的耐药性。5-FU诱导UM-SCC-23人鳞状细胞癌细胞中ERK和Akt激酶的活化，表明这种抗癌药物激活生存信号通路以及凋亡信号。在本课题组建立的5-FU耐药的UM-SCC-23细胞中，ERK和Akt信号被组成性激活。U 0126是MEK的抑制剂，MEK是ERK的上游激活剂。U 0126不能使耐药的UM-SCC-23细胞对5-FU诱导的凋亡性细胞死亡敏感。这与LY 294002形成鲜明对比，LY 294002是磷脂酰肌醇3-激酶的抑制剂，磷脂酰肌醇3-激酶是Akt的上游激活剂。LY 294002显著增强5-FU诱导的耐药UM-SCC-23细胞凋亡。这些结果表明Akt生存信号在鳞状细胞癌对5-FU治疗的耐药中起重要作用，提示Akt活性的改变可能为人5-FU耐药鳞状细胞癌的治疗提供新的策略。
5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent that inhibits the growth and initiates the apoptosis of epithelial tumors, including squamous cell carcinoma of the head and neck region. However, resistance to this drug is often observed in a clinical setting. The primary mode of action of 5-FU is believed to be the inhibition of thymidylate synthase. Overexpression of the enzymes involved in thymidine synthesis has been shown in some cases to be associated with resistance. However, the detailed mechanisms of resistance of squamous cell carcinoma are not fully understood. In the present study, we examined the involvement of survival signaling pathways in the resistance of squamous carcinoma cells to 5-FU. 5-FU induced the activation of the ERK and Akt kinases in UM-SCC-23 human squamous carcinoma cells, indicating that this anticancer drug activates survival signaling pathways as well as apoptotic signals. In 5-FU-resistant UM-SCC-23 cells established by our group, ERK and Akt signals were constitutively activated. U0126 is an inhibitor of MEK, which is an upstream activator for ERK. U0126 failed to sensitize resistant UM-SCC-23 cells to 5-FU-induced apoptotic cell death. This is in sharp contrast to LY294002, which is an inhibitor of phosphatidylinositol 3-kinase, an upstream activator for Akt. LY294002 drastically enhanced 5-FU-induced apoptotic cell death in resistant UM-SCC-23 cells. These results indicate that the Akt survival signal plays an important role in the resistance of squamous carcinoma cells to 5-FU treatment, and suggest that the modification of Akt activity might provide a new strategy for human 5-FU-resistant squamous carcinoma therapy.