Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1
Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1
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DOI：
10.1158/0008-5472.can-05-2002
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发表时间：
2005-11-15
期刊：
影响因子：
11.2
通讯作者：
Rebbaa, A
中科院分区：
文献类型：
--
作者：
Chu, F;Chou, PM;Rebbaa, A
不可逆的生长停滞（也称为衰老）最近已成为肿瘤抑制机制和癌症化疗结果的关键决定因素。以前，我们实验室的工作表明，细胞经历或逃避衰老的能力决定了它的命运，分别成为药物敏感或耐药性。在本研究中，我们假设长寿基因，凭借其抑制衰老的能力，可能有助于耐药性的发生。我们报告说，长寿基因sirt 1的表达增加在RNA和蛋白质水平上的所有五个耐药细胞系测试时，与他们的药物敏感的同行。此外，接受化疗药物治疗的癌症患者的活检组织也表达了高水平的这种分子。这些变化是sirt 1特有的，因为其家族其他成员的表达不受影响。更重要的是，小干扰RNA介导的sirt 1下调显著逆转了耐药表型，并减少了多药耐药分子P-糖蛋白的表达。这进一步证实了异位过表达的sirt 1，诱导表达的P-糖蛋白，使细胞耐阿霉素。总的来说，这些发现揭示了长寿基因sirt 1作为诊断和/或治疗癌症化疗耐药性的潜在靶点的新功能。他们还描述了一个原理证明，即与长寿有关的信号通路可能与导致癌症耐药性发展的信号通路有相似之处。
Irreversible growth arrest (also called senescence) has emerged recently as a tumor suppressor mechanism and a key determinant of cancer chemotherapy outcome. Previous,work from our laboratory suggested that the cellular ability to undergo or to escape senescence dictates its fate to become drug-sensitive or drug-resistant, respectively. In the present study, we made the hypothesis that longevity genes, by virtue of their abilitv to inhibit senescence, may contribute to the onset of drug resistance. We report that expression of the longevity gene sirt1 increased both at the RNA and protein levels in all the five drug-resistant cell lines tested when compared with their drug-sensitive counterparts. In addition, biopsies from cancer patients treated with chemotherapeutic agents also expressed high levels of this molecule. These changes were specific for sirt1 because the expression of other members of its family was not affected. More importantly, small interfering RNA-mediated down-regulation of sirt1 significantly reversed the resistance phenotype and reduced expression of the multidrug resistance molecule P-glycoprotein. This was further confirmed by ectopic overexpression of sirt1, which induced expression of P-glycoprotein and rendered cells resistant to doxorubicin. Collectively, these findings uncovered a novel function for the longevity gene sirt1 as a potential target for diagnosis and/or treatment of cancer resistance to chemotherapy. They also describe a proof of principle that signaling pathways implicated in longevity may share similarities with those leading to development of drug resistance in cancer.