Down-regulation of class II phosphoinositide 3-kinase α expression below a critical threshold induces apoptotic cell death
Down-regulation of class II phosphoinositide 3-kinase α expression below a critical threshold induces apoptotic cell death
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DOI：
10.1158/1541-7786.mcr-07-0262
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发表时间：
2008-04-01
影响因子：
5.2
通讯作者：
MacKeigan, Jeffrey P.
中科院分区：
文献类型：
--
作者：
Elis, Winfried;Triantafellow, Ellen;MacKeigan, Jeffrey P.
磷酸肌肽3-激酶（PI3K）家族成员共同控制多种细胞反应，包括增殖、生长、趋化和存活。这些不同的作用可以部分归因于这些脂质激酶的产物- 3'-磷酸肌苷所调节的广泛的下游效应。然而，由于存在多种PI3K酶同种异构体，增加了一层额外的复杂性。在过去的几年里，人们对I类和III类PI3K成员在细胞信号传导中的作用已经了解了很多，但对II类PI3K （C2 α， β和γ）完成的异构体特异性任务知之甚少。在这项研究中，我们使用了定量逆转录pcr和RNA干扰哺乳动物细胞来进一步了解这些较少研究的PI3K酶的功能。我们发现PI3K-C2 α，而不是PI3K-C2 β，在控制细胞存活中起重要作用，并且通过使用一组RNA干扰试剂，我们能够确定PI3K-C2 α mRNA水平的临界阈值，低于该阈值，凋亡程序就会通过固有的细胞死亡途径启动。此外，将PI3K-C2 α下调至自身不诱导凋亡的水平，可使细胞对抗癌药物紫杉醇（紫杉醇）敏感。最后，我们报告降低PI3K-C2 α的水平。在许多癌细胞系中，PI3K抑制剂降低了它们的增殖和细胞活力，这表明PI3K抑制剂不仅针对I类α亚型，也针对II类α亚型，可能有助于有效的抗癌策略。
Members of the phosphoinositide 3-kinase (PI3K) family collectively control multiple cellular responses, including proliferation, growth, chemotaxis, and survival. These diverse effects can partly be attributed to the broad range of downstream effectors being regulated by the products of these lipid kinases, the 3'-phosphoinositides. However, an additional layer of complexity is introduced by the existence of multiple PI3K enzyme isoforms. Much has been learned over the last years on the roles of the classes I and III PI3K members in cellular signaling, but little is known about the isoform-specific tasks done by the class II PI3Ks (C2 alpha, beta, and gamma). In this study, we used quantitative reverse transcription-PCR and RNA interference in mammalian cells to gain further insight into the function of these lesser studied PI3K enzymes. We find that PI3K-C2 alpha, but not PI3K-C2 beta, has an important role in controlling cell survival and by using a panel of RNA interference reagents, we were able to determine a critical threshold of PI3K-C2 alpha mRNA levels, below which the apoptotic program is switched on, via the intrinsic cell death pathway. In addition, knockdown of PI3K-C2 alpha to levels that by themselves do not induce apoptosis sensitize cells to the anticancer agent Taxol (paclitaxel). Lastly, we report that lowering the levels of PI3K-C2 alpha. in a number of cancer cell lines reduces their proliferation and cell viability, arguing that PI3K inhibitors targeting not only the class I alpha isoform but also class II alpha may contribute to an effective anticancer strategy.