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首页> 外文期刊>Journal of Cellular Physiology >Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs
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Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs

机译:小说的角色VMP1作为胰腺癌的修饰符肿瘤细胞对化疗药物的反应

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We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress-induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon.
机译:我们假设抑制分子调节细胞的适应性反应压力可以对抗阻力的胰腺癌细胞化疗药物。VMP1 autophagy-associated感蛋白,调节应激反应引起的在PDAC化疗药物。VMP1尤其过度不佳分化人类胰腺癌。药理研究表明,药物工作,在某种程度上,通过内质网压力反应,诱发VMP1表达式。同样,VMP1由已知的内质的诱导网压力活化剂。使用RNAi-based VMP1的对抗胰腺癌antitumoral应激反应代理。自噬和化疗抵抗甚至在chloroquin ATG5或Beclin 1 siRNAs或Beclin 1-binding VMP1突变体。网压力耦合的独立分子和细胞自噬机制。临床前研究表明异种移植表达的诱导和容易处理的形式VMP1显示增加耐吉西他滨治疗。VMP1作为潜在的治疗目标旨在敏化的组合疗法胰腺癌细胞化疗代理以及提供新颖的分子更好地理解这种现象的机制。

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