A stress-induced early innate response causes multidrug tolerance in melanoma.
A stress-induced early innate response causes multidrug tolerance in melanoma.
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作者：
获得性耐药性构成了有效癌症治疗的主要挑战，黑色素瘤也不例外。导致永久抗性的动力学知之甚少，但对于设计更好的治疗方法很重要。在这里，我们表明，药物暴露，缺氧或营养饥饿导致黑色素瘤细胞的早期先天性细胞反应，导致多药耐药，称为诱导耐药细胞（IDTC）。过渡到IDTC状态似乎是一个内在的压力反应，生存对不利的环境条件或药物暴露。该反应包括染色质重塑、信号级联的激活和与具有更高血管生成潜力和致瘤性的癌症干细胞性有关的标志物。这些变化的特征在于CD271表达的普遍增加，伴随着分化标志物如黑色素A和酪氨酸酶的丧失，醛脱氢酶（ALDH）活性增强和组蛋白脱甲基酶的上调。因此，IDTC显示H3K4me3、H3K27me3的丢失和H3K9me3的获得，表明差异基因的激活和抑制。IDTC州的药物假期允许恢复到亲代细胞，使它们对主要接触的药物重新敏感。然而，在持续的药物暴露后，IDTC最终转化为永久性和不可逆的耐药细胞。CD271或KDM5B的敲低显著降低了向IDTC状态的转变，但并不能阻止它。靶向IDTC对于可持续的疾病管理和预防获得性耐药性至关重要。
Acquired drug resistance constitutes a major challenge for effective cancer therapies with melanoma being no exception. The dynamics leading to permanent resistance are poorly understood but are important to design better treatments. Here we show that drug exposure, hypoxia or nutrient starvation leads to an early innate cell response in melanoma cells resulting in multidrug resistance, termed induced drug-tolerant cells (IDTCs). Transition into the IDTC state seems to be an inherent stress reaction for survival toward unfavorable environmental conditions or drug exposure. The response comprises chromatin remodeling, activation of signaling cascades and markers implicated in cancer stemness with higher angiogenic potential and tumorigenicity. These changes are characterized by a common increase in CD271 expression concomitantly with loss of differentiation markers such as melan-A and tyrosinase, enhanced aldehyde dehydrogenase (ALDH) activity and upregulation of histone demethylases. Accordingly, IDTCs show a loss of H3K4me3, H3K27me3 and gain of H3K9me3 suggesting activation and repression of differential genes. Drug holidays at the IDTC state allow for reversion into parental cells re-sensitizing them to the drug they were primarily exposed to. However, upon continuous drug exposure IDTCs eventually transform into permanent and irreversible drug-resistant cells. Knockdown of CD271 or KDM5B decreases transition into the IDTC state substantially but does not prevent it. Targeting IDTCs would be crucial for sustainable disease management and prevention of acquired drug resistance.
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影响因子：
64.5
作者：
Roesch A;Fukunaga-Kalabis M;Schmidt EC;Zabierowski SE;Brafford PA;Vultur A;Basu D;Gimotty P;Vogt T;Herlyn M
通讯作者：
Herlyn M
DOI：
10.4161/cc.21476
发表时间：
2012-08-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Alla V;Kowtharapu BS;Engelmann D;Emmrich S;Schmitz U;Steder M;Pützer BM
通讯作者：
Pützer BM
影响因子：
11.2
作者：
Frank, NY;Margaryan, A;Frank, MH
通讯作者：
Frank, MH
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Roesch A;Vultur A;Bogeski I;Wang H;Zimmermann KM;Speicher D;Körbel C;Laschke MW;Gimotty PA;Philipp SE;Krause E;Pätzold S;Villanueva J;Krepler C;Fukunaga-Kalabis M;Hoth M;Bastian BC;Vogt T;Herlyn M
通讯作者：
Herlyn M