Activity of any class IA PI3K isoform can sustain cell proliferation and survival
Activity of any class IA PI3K isoform can sustain cell proliferation and survival
复制标题
DOI：
10.1073/pnas.0906461107
复制
发表时间：
2010-06-22
影响因子：
11.1
通讯作者：
Vanhaesebroeck, Bart
中科院分区：
文献类型：
--
作者：
Foukas, Lazaros C.;Berenjeno, Inma M.;Vanhaesebroeck, Bart
用于肿瘤学的 PI3K 小分子抑制剂主要针对 I 类 PI3K，包括 p110 α、β、γ 和 δ 亚型，其中只有 p110 α 在癌症中发生突变。为了评估 I 类 PI3K 亚型在细胞增殖和存活中的作用，我们生成了永生化小鼠白细胞和成纤维细胞模型，其中通过遗传和药理学方法灭活了 I 类 PI3K。在 IL3 依赖性造血祖细胞（表达所有四种 I 类 PI3K 同工型）中，p110 α 或 p110 δ 的基因失活不会影响细胞增殖或存活，也不会对 p110 β 或 p110 γ 失活敏感。 p110 α 和 p110 δ 复合失活后，会消除超过 90% 的 p85 相关 PI3K 活性，显着的是，细胞继续有效增殖，而 p110 β 在信号传导和细胞存活中发挥着重要作用。此外，在 I 类 PI3K 活性减弱的情况下，来自 ERK 通路的输入对于细胞存活变得重要。在小鼠胚胎中也进行了类似的观察。成纤维细胞（主要表达 p110 α 和 p110 β），其中 p110 α 或 p110 β 可以作为单一亚型维持细胞增殖。总而言之，这些数据表明 I 类 PI3K 总活性的一小部分足以维持细胞存活和增殖。持续抑制选定的 PI3K 同工型可以使剩余的同工型与它们通常不参与的上游信号传导途径偶联。 IA 类 PI3K 异构体在持续 PI3K 抑制后的这种功能冗余对于 PI3K 抑制剂在癌症中的开发和使用具有重要意义。
Small molecule inhibitors of PI3K for oncology mainly target the class I PI3Ks, comprising the p110 alpha, beta, gamma, and delta isoforms, of which only p110 alpha is mutated in cancer. To assess the roles of class I PI3K isoforms in cell proliferation and survival, we generated immortalized mouse leukocyte and fibroblast models in which class I PI3Ks were inactivated by genetic and pharmacological approaches. In IL3-dependent hemopoietic progenitor cells (which express all four class I PI3K isoforms), genetic inactivation of either p110 alpha or p110 delta did not affect cell proliferation or survival or sensitize to p110 beta or p110 gamma inactivation. Upon compound inactivation of p110 alpha and p110 delta, which removed >90% of p85-associated PI3K activity, remarkably, cells continued to proliferate effectively, with p110 beta assuming an essential role in signaling and cell survival. Furthermore, under these conditions of diminished class I PI3K activity, input from the ERK pathway became important for cell survival. Similar observations were made in mouse embryonic. broblasts (which mainly express p110 alpha and p110 beta) in which p110 alpha or p110 beta could sustain cell proliferation as a single isoform. Taken together, these data demonstrate that a small fraction of total class I PI3K activity is sufficient to sustain cell survival and proliferation. Persistent inhibition of selected PI3K isoforms can allow the remaining isoform( s) to couple to upstream signaling pathways in which they are not normally engaged. Such functional redundancy of class IA PI3K isoforms upon sustained PI3K inhibition has implications for the development and use of PI3K inhibitors in cancer.