Acquired resistance to 5-fluorouracil via HSP90/Src-mediated increase in thymidylate synthase expression in colon cancer.
Acquired resistance to 5-fluorouracil via HSP90/Src-mediated increase in thymidylate synthase expression in colon cancer.
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DOI：
10.18632/oncotarget.5327
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发表时间：
2015-10-20
期刊：
影响因子：
--
通讯作者：
Lee HY
中科院分区：
文献类型：
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作者：
Ahn JY;Lee JS;Min HY;Lee HY
5-氟尿嘧啶（5-FU）是治疗胃肠道恶性肿瘤的一线化疗药物之一，但疗效有限。胸苷酸合成酶（TYMS）的表达与5-FU耐药有关。在这里，我们证明了增强的HSP 90功能和随后的Src激活诱导TYMS的表达和获得性耐药5-FU结肠癌。我们发现，持续的5-FU治疗给予5-FU敏感的HCT 116结肠癌细胞上皮间质转化（EMT）的形态，分子和行为特征，有助于出现获得性耐药5-FU。HCT 116/R是一种对5-FU具有获得性耐药的HCT 116结肠癌细胞亚系，其表现出HSP 90客户蛋白的表达和激活增加以及TYMS的转录上调。在HCT 116细胞中强制过表达HSP 90或组成型活性Src增加TYMS表达。相反，药物阻断HCT 116/R细胞中的HSP 90或Src有效地抑制了体外5-FU耐药性和体内异种移植肿瘤生长、血行扩散和转移性肿瘤发展的变化。本研究提示HSP 90-Src通路在调控TYMS表达和获得5-FU抗性中具有新的功能。因此，靶向这一途径的治疗可能是克服结肠癌5-FU耐药的有效临床策略。
5-fluorouracil (5-FU), one of the first-line chemotherapeutic agents for the treatment of gastrointestinal malignancies, has shown limited efficacy. The expression of thymidylate synthase (TYMS) has been reported to be associated with the resistance to 5-FU. Here, we demonstrate that the enhanced HSP90 function and subsequent activation of Src induce expression of TYMS and acquired resistance to 5-FU in colon cancer. We show that the persistent 5-FU treatment granted 5-FU-sensitive HCT116 colon cancer cells morphologic, molecular, and behavioral characteristic of the epithelial-mesenchymal transition (EMT), contributing to emergence of acquired resistance to 5-FU. HCT116/R, a HCT116 colon cancer cell subline carrying acquired resistance to 5-FU, showed increased expression and activation of HSP90's client proteins and transcriptional up-regulation of TYMS. Forced overexpression of HSP90 or constitutive active Src in HCT116 cells increased TYMS expression. Conversely, pharmacological blockade of HSP90 or Src in HCT116/R cells effectively suppressed the changes involved in 5-FU resistance in vitro and xenograft tumor growth, hematogenous spread, and metastatic tumor development in vivo. This study suggests a novel function of HSP90-Src pathway in regulation of TYMS expression and acquisition of 5-FU resistance. Thus, therapeutics targeting this pathway may be an effective clinical strategy to overcome 5-FU resistance in colon cancer.