The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis
The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis
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DOI：
10.1038/onc.2012.92
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发表时间：
2013-02-07
期刊：
影响因子：
8
通讯作者：
Goping, I. S.
中科院分区：
文献类型：
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作者：
Veldhoen, R. A.;Banman, S. L.;Goping, I. S.
抗有丝分裂剂如紫杉醇和多西他赛广泛用于治疗乳腺癌、卵巢癌和肺癌。虽然紫杉醇诱导细胞凋亡，这种药物也调节自噬。自噬如何影响紫杉醇活性尚不清楚。我们发现紫杉醇通过依赖于细胞周期阶段的两种不同机制抑制自噬。在有丝分裂细胞中，紫杉醇阻断了III类磷脂酰肌醇3激酶（Vps 34）的激活，Vps 34是自噬体形成的关键起始物。在非有丝分裂紫杉醇处理的细胞中，产生自噬体，但其运动和成熟受到抑制。化学或遗传阻断自噬体形成减少紫杉醇诱导的细胞死亡，表明自噬体积累使细胞对紫杉醇毒性敏感。与这些观察结果一致，我们确定了表达降低水平的自噬起始基因的原发性乳腺肿瘤对紫杉烷治疗具有抗性，确定了临床化疗抗性的可能机制和预后标志物。Oncogene（2013）32，736-746; doi：10.1038/onc.2012.92; 2012年3月19日在线发表
Anti-mitotic agents such as paclitaxel and docetaxel are widely used for the treatment of breast, ovarian and lung cancers. Although paclitaxel induces apoptosis, this drug also modulates autophagy. How autophagy affects paclitaxel activity, is unclear. We discovered that paclitaxel inhibited autophagy through two distinct mechanisms dependent on cell cycle stage. In mitotic cells, paclitaxel blocked activation of the class III phosphatidyl inositol 3 kinase, Vps34, a critical initiator of autophagosome formation. In non-mitotic paclitaxel-treated cells, autophagosomes were generated but their movement and maturation was inhibited. Chemically or genetically blocking autophagosome formation diminished paclitaxel-induced cell death suggesting that autophagosome accumulation sensitized cells to paclitaxel toxicity. In line with these observations, we identified that primary breast tumors that expressed diminished levels of autophagy-initiating genes were resistant to taxane therapy, identifying possible mechanisms and prognostic markers of clinical chemotherapeutic resistance. Oncogene (2013) 32, 736-746; doi:10.1038/onc.2012.92; published online 19 March 2012