Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells
Histone deacetylase inhibitor enhances 5-fluorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells
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DOI：
10.1158/1535-7163.mct-06-0419
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发表时间：
2006-12-01
影响因子：
5.7
通讯作者：
Bang, Yung-Jue
中科院分区：
文献类型：
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作者：
Lee, Ju-Hee;Park, Jung-Hyun;Bang, Yung-Jue
胸苷酸合成酶（TS）过表达是人类癌细胞5-氟尿嘧啶（5-FU）耐药的关键决定因素。5-FU治疗也可使TS急剧上调，因此，靶向TS下调的新策略在调节5-FU耐药性方面似乎很有前景。在这里，我们报告组蛋白去乙酰化酶抑制剂可以通过下调TS逆转5-FU耐药。通过使用cDNA微阵列和验证实验，我们发现，抑制素A降低TS mRNA和TS蛋白的表达。共处理与抑制素A和放线菌酮恢复TS mRNA的表达，表明TS mRNA通过新的蛋白质合成被抑制。另一方面，TS蛋白的表达显着降低低剂量的阿司他丁A（50 nmol/L）。TS蛋白与热休克蛋白（Hsp）复合物发生相互作用，而抑制素A诱导Hsp 90乙酰化，增强Hsp 70与TS的结合，导致TS蛋白被蛋白酶体降解。值得注意的是，与TS蛋白下调一致，用低剂量阿司他汀A和5-FU联合治疗增强了5-FU耐药癌细胞中5-FU介导的细胞毒性。我们得出结论，使用组蛋白去乙酰化酶抑制剂的组合方法可能有助于克服5-FU耐药性。
Thymidylate synthase (TS) overexpression is a key determinant of 5-fluorouracil (5-FU) resistance in human cancer cells. TS is also acutely up-regulated with 5-FU treatment, and, thus, novel strategies targeting TS downregulation seem to be promising in terms of modulating 5-FU resistance. Here, we report that histone deacetylase inhibitors can reverse 5-FU resistance by down-regulating TS. By using cDNA microarrays and validation experiments, we found that trichostatin A reduced the expression of both TS mRNA and TS protein. Cotreatment with trichostatin A and cycloheximide restored TS mRNA expression, suggesting that TS mRNA is repressed through new protein synthesis. On the other hand, TS protein expression was significantly reduced by lower doses of trichostatin A (50 nmol/L). Mechanistically, TS protein was found to interact with heat shock protein (Hsp) complex, and trichostatin A treatment induced chaperonic Hsp90 acetylation and subsequently enhanced Hsp70 binding to TS, which led to the proteasomal degradation of TS protein. Of note, combined treatment with low-dose trichostatin A and 5-FU enhanced 5-FU mediated cytotoxicity in 5-FU-resistant cancer cells in accordance with TS protein down-regulation. We conclude that a combinatorial approach using histone deacetylase inhibitors may be useful at overcoming 5-FU resistance.