Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation.
Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation.
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DOI：
10.1038/cddis.2015.137
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发表时间：
2015-06-04
影响因子：
9
通讯作者：
Brunner T
中科院分区：
文献类型：
--
作者：
Brockmann A;Bluwstein A;Kögel A;May S;Marx A;Tschan MP;Brunner T
虽然许多抗癌治疗的目标是针对肿瘤细胞的死亡，但肿瘤细胞中复杂的耐药机制阻止了细胞死亡的诱导。尤其是谷胱甘肽-S-转移酶家族的酶代表了众所周知的解毒机制，它限制了化疗药物在肿瘤细胞中的作用。具体地说，P1类GST(GSTP1-1)在结直肠肿瘤细胞中过表达，并使它们对各种药物产生耐药性。因此，GSTP1-1已成为重要的治疗靶点。我们最近发现，新型抗感染药物噻唑烷类药物通过依赖GSTP1-1的方式诱导结直肠肿瘤细胞凋亡，从而绕过GSTP1-1介导的耐药。在本研究中，我们详细研究了噻唑胺诱导结直肠肿瘤细胞凋亡的可能机制。噻唑烷诱导p38和Jun激酶的激活，这是噻唑烷诱导细胞死亡所必需的。这些MAP激酶的激活导致促凋亡的Bim和Puma的表达增加，从而诱导和隔离Mcl-1和Bclxl，从而诱导线粒体的凋亡途径。有趣的是，虽然细胞内谷胱甘肽水平的增加导致对顺铂的耐药性增加，但它通过促进Jun激酶的激活和Bim的诱导，使结直肠肿瘤细胞对噻唑胺诱导的细胞凋亡敏感。因此，通过特异性靶向肿瘤耐药机制，如GSTP1-1，噻唑类化合物可能代表了一类有趣的新型抗肿瘤药物。
While many anticancer therapies aim to target the death of tumor cells, sophisticated resistance mechanisms in the tumor cells prevent cell death induction. In particular enzymes of the glutathion-S-transferase (GST) family represent a well-known detoxification mechanism, which limit the effect of chemotherapeutic drugs in tumor cells. Specifically, GST of the class P1 (GSTP1-1) is overexpressed in colorectal tumor cells and renders them resistant to various drugs. Thus, GSTP1-1 has become an important therapeutic target. We have recently shown that thiazolides, a novel class of anti-infectious drugs, induce apoptosis in colorectal tumor cells in a GSTP1-1-dependent manner, thereby bypassing this GSTP1-1-mediated drug resistance. In this study we investigated in detail the underlying mechanism of thiazolide-induced apoptosis induction in colorectal tumor cells. Thiazolides induce the activation of p38 and Jun kinase, which is required for thiazolide-induced cell death. Activation of these MAP kinases results in increased expression of the pro-apoptotic Bcl-2 homologs Bim and Puma, which inducibly bind and sequester Mcl-1 and Bcl-xL leading to the induction of the mitochondrial apoptosis pathway. Of interest, while an increase in intracellular glutathione levels resulted in increased resistance to cisplatin, it sensitized colorectal tumor cells to thiazolide-induced apoptosis by promoting increased Jun kinase activation and Bim induction. Thus, thiazolides may represent an interesting novel class of anti-tumor agents by specifically targeting tumor resistance mechanisms, such as GSTP1-1.