Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin.
Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin.
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DOI：
10.1158/1535-7163.1605.3.12
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发表时间：
2004-12
影响因子：
5.7
通讯作者：
David J. VanderWeele;R. Zhou;C. Rudin
中科院分区：
文献类型：
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作者：
David J. VanderWeele;R. Zhou;C. Rudin
化疗药物通过作用于多个细胞内靶点诱导癌细胞凋亡。最近的观察表明，一个一致的细胞反应不同类别的化疗药物是糖酵解代谢的下调。在几种模型中，糖酵解活性的抑制与凋亡诱导有关。丝氨酸/苏氨酸激酶Akt（蛋白激酶B）促进糖酵解代谢和存活，并且这些功能已被证明是相关的。由于其在糖酵解和存活中的关键作用，我们研究了Akt在细胞毒性剂的细胞应答中的功能。在暴露于几种化疗剂中的任何一种后，内源性Akt活性的初始上调被迅速抑制。使用含有组成型活性豆蔻酰化Akt，显性负激酶死亡Akt或空载体对照的细胞，我们在这里表明，Akt激活显着增加对微管导向剂，包括长春新碱，秋水仙碱和紫杉醇的耐药性。Akt也维持增加的糖酵解速率以响应抗微管治疗。雷帕霉素抑制Akt介导的糖酵解和治疗抗性的维持，表明这些作用依赖于雷帕霉素的哺乳动物靶标（mTOR）。此外，活化的mTOR突变体赋予对抗微管剂的抗性。总之，这些观察结果表明，激活Akt-mTOR信号通路可以增加葡萄糖利用率，并促进对不直接靶向代谢调节的化疗药物的耐药性。这些数据提供了对抗癌疗法的潜在协同组合的洞察。
Chemotherapeutic agents induce apoptosis in cancer cells through effects on multiple intracellular targets. Recent observations suggest that a consistent cellular response to chemotherapeutic agents of disparate classes is down-regulation of glycolytic metabolism. Inhibition of glycolytic activity has been linked to apoptotic induction in several models. The serine/threonine kinase Akt (protein kinase B) promotes both glycolytic metabolism and survival, and these functions have been shown to be linked. Because of its key role in both glycolysis and survival, we examined the function of Akt in the cellular response to cytotoxic agents. Following exposure to any of several chemotherapeutic agents, an initial up-regulation in endogenous Akt activity is rapidly suppressed. Using cells containing constitutively active myristoylated Akt, dominant-negative kinase-dead Akt, or an empty vector control, we show here that Akt activation markedly increases resistance to microtubule-directed agents, including vincristine, colchicine, and paclitaxel. Akt also maintains increased glycolytic rate in response to antimicrotubule treatment. Rapamycin inhibits Akt-mediated maintenance of glycolysis and therapeutic resistance, indicating that these effects are dependent on mammalian target of rapamycin (mTOR). Furthermore, an activated mTOR mutant confers resistance to antimicrotubule agents. Taken together, these observations suggest that activation of the Akt-mTOR signaling pathway can augment glucose utilization and promote resistance to chemotherapeutic agents that do not directly target metabolic regulation. These data provide insight into potentially synergistic combinations of anticancer therapies.