Autophagy, an Achilles' heel AKTing against cancer?
Autophagy, an Achilles' heel AKTing against cancer?
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DOI：
10.4161/auto.5.3.7827
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发表时间：
2009-04-01
期刊：
影响因子：
13.3
通讯作者：
Lin, Kui
中科院分区：
文献类型：
--
作者：
Degtyarev, Michael;De Maziere, Ann;Lin, Kui
Akt 已成为一种有吸引力的癌症治疗靶点，在细胞存活、生长、增殖和代谢中发挥着核心作用。 Akt 抑制剂临床成功的关键是在没有无法忍受的副作用的情况下实现最大可能的抗肿瘤功效。在我们最近的工作中，我们表明，尽管 Akt 抑制并不总是诱导明显的细胞凋亡反应，但自噬是对泛 Akt 敲低或 PI3K/Akt 途径的选择性小分子抑制剂更容易检测到的反应。自噬是大量溶酶体降解和细胞质物质和细胞器回收的分解代谢过程，可以为细胞在应激条件下提供暂时的生存机制，但也可以使细胞在特定情况下容易遭受多种形式的细胞死亡。我们假设 Akt 抑制诱导的自噬可能会使肿瘤细胞对针对溶酶体降解过程后期步骤的药物敏感。事实上，干扰溶酶体降解功能的药物与 Akt 抑制相结合可加速细胞死亡，并在临床前模型中促进肿瘤完全缓解。这些发现表明，操纵自噬反应可能是提高 Akt 抑制剂治疗效果的一种有前景的策略。
Akt has emerged as an attractive cancer therapeutic target with a central role in cell survival, growth, proliferation and metabolism. A key to the clinical success of Akt inhibitors is the maximal possible antitumor efficacy achievable without intolerable side effects. In our recent work, we show that although Akt inhibition does not always induce a clear apoptotic response, autophagy is a more readily detectable response to pan-Akt knockdown or selective small molecule inhibitors of the PI3K/Akt pathway. Autophagy is a catabolic process of bulk lysosomal degradation and recycling of cytoplasmic material and organelles, which can provide a temporary survival mechanism for cells under stress conditions, but can also make cells vulnerable to several forms of cell death under specific circumstances. We hypothesize that autophagy induced by Akt inhibition may sensitize tumor cells to agents targeting the later steps of this lysosomal degradation process. Indeed, agents that interfere with the lysosomal degradation function could precipitate cell death when combined with Akt inhibition and promote complete tumor remissions in preclinical models. These findings suggest that manipulating the autophagic response may be a promising strategy to increase the therapeutic efficacy of Akt inhibitors.