Tumor Biology Group, Regional Cancer Program of the Sudbury Regional Hospital, Sudbury, Ontario, Canada.
PLoS One. 2011 Jan 31;6(1):e14614. doi: 10.1371/journal.pone.0014614.
Akt/PKB is a promising anticancer therapeutic target, since abnormally elevated Akt activity is directly correlated to tumor development, progression, poor prognosis and resistance to cancer therapies. Currently, the unique role of each Akt isoform and their relevance to human breast cancer are poorly understood.
METHODOLOGY/PRINCIPAL FINDINGS: We previously found that Akt1, 2 and 3 are localized at specific subcellular compartments (the cytoplasm, mitochondria and nucleus, respectively), raising the possibility that each isoform may have unique functions and employ different regulation mechanisms. By systematically studying Akt-ablated MDA-MB231 breast cancer cells with isoform-specific siRNA, we here show that Akt2 is the most relevant isoform to cell proliferation and survival in our cancer model. Prolonged ablation of Akt2 with siRNA resulted in cell-cycle arrest in G0/G1 by downregulating Cdk2 and cyclin D, and upregulating p27. The analysis of the Akt downstream signaling pathways suggested that Akt2 specifically targets and activates the p70S6K signaling pathway. We also found that Akt2 ablation initially resulted in an increase in the mitochondrial volume concomitantly with the upregulation of PGC-1α, a regulator of mitochondrial biogenesis. Prolonged ablation of Akt2, but not Akt1 or Akt3, eventually led to cell death by autophagy of the mitochondria (i.e., mitophagy).
CONCLUSIONS/SIGNIFICANCE: Collectively, our data demonstrates that Akt2 augments cell proliferation by facilitating cell cycle progression through the upregulation of the cell cycle engine, and protects a cell from pathological autophagy by modulating mitochondrial homeostasis. Our data, thus, raises the possibility that Akt2 can be an effective anticancer target for the control of (breast) cancer.
Akt/PKB 是一种很有前途的抗癌治疗靶点，因为异常升高的 Akt 活性与肿瘤的发展、进展、不良预后和对癌症治疗的耐药性直接相关。目前，每种 Akt 同工型的独特作用及其与人类乳腺癌的相关性还知之甚少。
方法/主要发现：我们之前发现 Akt1、2 和 3 分别定位于特定的亚细胞隔室（细胞质、线粒体和细胞核），这表明每个同工型可能具有独特的功能，并采用不同的调节机制。通过系统地研究具有同工型特异性 siRNA 的 Akt 缺失型 MDA-MB231 乳腺癌细胞，我们在此表明 Akt2 是我们癌症模型中与细胞增殖和存活最相关的同工型。用 siRNA 长时间敲除 Akt2 会通过下调 Cdk2 和 cyclin D 并上调 p27 导致细胞周期停滞在 G0/G1 期。对 Akt 下游信号通路的分析表明，Akt2 特异性靶向并激活 p70S6K 信号通路。我们还发现，Akt2 缺失最初会导致线粒体体积增加，同时上调 PGC-1α，这是线粒体生物发生的调节因子。长时间敲除 Akt2（而不是 Akt1 或 Akt3）最终会通过线粒体自噬（即线粒体噬）导致细胞死亡。
结论/意义：总的来说，我们的数据表明，Akt2 通过上调细胞周期引擎促进细胞周期进程来增强细胞增殖，并通过调节线粒体稳态来保护细胞免受病理性自噬。因此，我们的数据提出了 Akt2 可能是控制（乳腺癌）癌症的有效抗癌靶点的可能性。
