Hypoxia induces resistance to 5-fluorouracil in oral cancer cells via G1 phase cell cycle arrest
Hypoxia induces resistance to 5-fluorouracil in oral cancer cells via G1 phase cell cycle arrest
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DOI：
10.1016/j.oraloncology.2008.04.002
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发表时间：
2009-02-01
期刊：
影响因子：
4.8
通讯作者：
Shintani, Satoru
中科院分区：
文献类型：
--
作者：
Yoshiba, Sayaka;Ito, Daisuke;Shintani, Satoru
恶性肿瘤在体内暴露于不同水平的缺氧条件。众所周知，缺氧条件下的肿瘤细胞对化疗具有抗性。为探讨低氧诱导口腔鳞癌细胞耐药的机制，我们观察了低氧对口腔鳞癌细胞株5-氟尿嘧啶（5-FU）耐药的影响。根据低氧条件下的增殖活性，将口腔鳞癌细胞分为低氧抵抗（HR）和低氧敏感（HS）两组。缺氧可抑制HS细胞的生长，使细胞周期阻滞于G（1）期。低氧条件下5-FU对HS细胞活力的影响显著降低，而不诱导化疗耐药相关蛋白P-糖蛋白。然而，HR细胞的增殖，细胞周期和5-FU敏感性不受缺氧的影响。低氧诱导因子（HIF）-1 α在所有OSCC细胞系中均被低氧诱导，但在HS细胞中在48 h内减少。缺氧可使HS细胞p21、p27表达增强，CyclinD表达降低。然而，这些蛋白质的表达是组成性的HR细胞在48小时缺氧培养。缺氧可降低HS细胞中哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化。从这些发现中，我们得出结论，HS OSCC细胞获得5-FU耐缺氧通过G（1）/S转换通过上调细胞周期抑制剂。(C)2008爱思唯尔有限公司保留所有权利。
Malignant tumors are exposed to various levels of hypoxic condition in vivo. It has been known that tumor cells under hypoxia are resistant to chemotherapies. To clarify the mechanism of the hypoxia-induced chemoresistance, we evaluated the effects of hypoxia on the resistance of oral squamous cell carcinoma (OSCC) cell tines to 5-fluorouracil (5-FU). OSCC cells were divided to two groups by the proliferation activity under hypoxic condition; hypoxia-resistant (HR) and hypoxia-sensitive (HS) cells. Growth of HS cells were inhibited by hypoxia and introduced to G(1) arrest in cell cycle. 5-FU effect on HS cell viability was markedly reduced in hypoxic condition without an induction of chemoresistant related protein, P-glycoprotein. However, proliferation, cell cycle, and 5-FU sensitivity of HR cells were not affected by hypoxia. Hypoxia-inducible factor (HIF)-1 alpha was induced by hypoxia in all OSCC cell lines, but diminished in HS cells within 48 h. Expression of p21 and p27 was strongly augmented and CyclinD expression was reduced by hypoxia in HS cells. However, the expression of these proteins was constitutive in HR cells during 48 h hypoxic culture. Phosphorylation of mammalian target of rapamycin (mTOR) was reduced by hypoxia in HS cells. From these findings, we concluded that HS OSCC cells acquire 5-FU resistance under hypoxia by G(1)/S transition through an upregulation of cell cycle inhibitors. (C) 2008 Elsevier Ltd. All rights reserved.