Both p110α and p110β isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor.
Both p110α and p110β isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor.
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DOI：
10.1042/bj20111741
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发表时间：
2012-02-15
期刊：
影响因子：
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通讯作者：
Vanhaesebroeck B
中科院分区：
文献类型：
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作者：
Berenjeno IM;Guillermet-Guibert J;Pearce W;Gray A;Fleming S;Vanhaesebroeck B
PI3K(磷酸肌醇3-激酶)通路在癌症中通常被激活，这是由于肿瘤抑制基因PTEN(10号染色体上缺失的磷酸酶和张力蛋白同源物)失活的结果，PTEN是PI3K信号的主要负调控因子。与PTEN的这一重要作用相一致的是，PTEN缺失等位基因杂合子的小鼠(PTEN+/−小鼠)会自发地在多个器官中患上各种肿瘤。PTEN是一种对PtdIns(3，4，5)P3具有选择性的磷酸酶，由PI3K的I类亚型(p110α、p110β、p110γ和p110δ)产生。以往的研究表明，PTEN缺失的癌细胞株主要依赖于p110β，而p110β而不是p110α控制着由PTEN缺失所驱动的小鼠前列腺癌的发展。在本研究中，我们研究了在肿瘤中普遍表达的p110PTEN是否也能与α功能相互作用。利用模拟p110α或p110β选择性抑制剂全身给药的小鼠遗传模型，我们证实了p110β的失活，而不是p110α的失活，抑制了PTEN+/−小鼠的前列腺癌的发展，但也发现p110α的失活对PTEN缺失引发的肾小球肾炎、嗜铬细胞瘤和甲状腺癌具有保护作用。这表明p110PTEN可以调节α缺失在疾病和肿瘤发生中的作用。在原代和永生化的小鼠成纤维细胞系中，p110α和p110β都控制了PtdIns(3，4，5)P3的稳态水平和杂合性缺失引起的Akt信号转导。在原代小鼠组织中，未发现PtdIns(3，4，5)P3水平和PI3K/PTEN基因与肿瘤发生的相关性。综上所述，我们的研究结果表明，p110α或p110β的失活都可以抵消PTEN失活的影响。这些发现对PI3K靶向治疗癌症的潜在意义进行了讨论。
The PI3K (phosphoinositide 3-kinase) pathway is commonly activated in cancer as a consequence of inactivation of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K signalling. In line with this important role of PTEN, mice that are heterozygous for a PTEN-null allele (PTEN+/− mice) spontaneously develop a variety of tumours in multiple organs. PTEN is a phosphatase with selectivity for PtdIns(3,4,5)P3, which is produced by the class I isoforms of PI3K (p110α, p110β, p110γ and p110δ). Previous studies indicated that PTEN-deficient cancer cell lines mainly depend on p110β, and that p110β, but not p110α, controls mouse prostate cancer development driven by PTEN loss. In the present study, we investigated whether the ubiquitously expressed p110α can also functionally interact with PTEN in cancer. Using genetic mouse models that mimic systemic administration of p110α- or p110β-selective inhibitors, we confirm that inactivation of p110β, but not p110α, inhibits prostate cancer development in PTEN+/− mice, but also find that p110α inactivation protects from glomerulonephritis, pheochromocytoma and thyroid cancer induced by PTEN loss. This indicates that p110α can modulate the impact of PTEN loss in disease and tumourigenesis. In primary and immortalized mouse fibroblast cell lines, both p110α and p110β controlled steady-state PtdIns(3,4,5)P3 levels and Akt signalling induced by heterozygous PTEN loss. In contrast, no correlation was found in primary mouse tissues between PtdIns(3,4,5)P3 levels, PI3K/PTEN genotype and cancer development. Taken together, our results from the present study show that inactivation of either p110α or p110β can counteract the impact of PTEN inactivation. The potential implications of these findings for PI3K-targeted therapy of cancer are discussed.