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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >PTEN-deficient cancers depend on PIK3CB
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PTEN-deficient cancers depend on PIK3CB

机译：PTEN缺陷型癌症取决于PIK3CB

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摘要

Deregulation of the PI3K signaling pathway is observed in many human cancers and occurs most frequently through loss of PTEN phosphatase tumor suppressor function or through somatic activating mutations in the Class IA PI3K, PIK3CA. Tumors harboring activated p110α, the protein product of PIK3CA, require p110α activity for growth and survival and hence are expected to be responsive to inhibitors of its lipid kinase activity. Whether PTEN-deficient cancers similarly depend on p110α activity to sustain activation of the PI3K pathway has been unclear. In this study, we used a single-vector lentiviral inducible shRNA system to selectively inactivate the three Class IA PI3Ks, PIK3CA. PIK3CB, and PIK3CD. to determine which PI3K isoforms are responsible for driving the abnormal proliferation of PTEN-deficient cancers. Down-regulation of PIK3CA in colorectal cancer cells harboring mutations in PIK3CA inhibited downstream PI3K signaling and cell growth. Surprisingly, PIK3CA depletion affected neither PI3K signaling nor cell growth in 3 PTEN-deficient cancer cell lines. In contrast, down-regulation of the PIK3CB isoform, which encodes p110β, resulted in pathway inactivation and subsequent inhibition of growth in both cell-based and in vivo settings. This essential function of PIK3CB in PTEN-deficient cancer cells required its lipid kinase activity. Our findings demonstrate that although p110α activation is required to sustain the proliferation of established PWC3C4-mutant tumors, PTEN-deficient tumors are dependent instead on p110β signaling. This unexpected finding demonstrates the need to tailor therapeutic approaches to the genetic basis of PI3K pathway activation to achieve optimal treatment response.
机译：在许多人类癌症中观察到PI3K信号通路的失调，并且最经常通过PTEN磷酸酶肿瘤抑制功能的丧失或IA类PI3K，PIK3CA中的体细胞激活突变而发生。带有活化的p110α（PIK3CA的蛋白质产物）的肿瘤需要p110α活性才能生长和存活，因此有望对其脂质激酶活性的抑制剂产生反应。 PTEN缺陷型癌症是否同样依赖于p110α活性来维持PI3K途径的激活尚不清楚。在这项研究中，我们使用了单载体慢病毒诱导型shRNA系统选择性地灭活了三个IA类PI3K PIK3CA。 PIK3CB和PIK3CD。确定哪些PI3K同工型负责驱动PTEN缺陷型癌症的异常增殖。在具有PIK3CA突变的大肠癌细胞中，PIK3CA的下调抑制了下游PI3K信号传导和细胞生长。出人意料的是，PIK3CA耗竭既不影响PI3K信号传导，也不影响3种PTEN缺陷癌细胞系中的细胞生长。相比之下，编码p110β的PIK3CB亚型的下调会导致通路失活，并随后在基于细胞和体内的环境中抑制生长。 PIK3CB在PTEN缺陷型癌细胞中的这种基本功能需要其脂质激酶活性。我们的发现表明，尽管需要p110α激活来维持已建立的PWC3C4突变型肿瘤的增殖，但PTEN缺陷型肿瘤却依赖于p110β信号传导。这一出乎意料的发现表明，有必要针对PI3K途径激活的遗传基础量身定制治疗方法，以实现最佳治疗反应。

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